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Neuropeptides and their classification

Neuropeptides and their Classification

Mammalian Neuropeptides and Neuropeptide Families

Due to the history of the discovery of neuropeptides and endocrine peptides, their location of synthesis and targets, the classification of these types of peptides is somewhat tricky. This has led to a few classification approaches. Some of them are listed below. The new fields of brain research and neuroscience will surly add more peptides to this list in the coming years.


Classification of bioactive peptides

 

·         Hypthalamic releasing factors

o   CRH: corticotrophin releasing hormone

o   GHRH: growth hormone releasing hormone

o   GnRH: gonadotropin releasing hormone

o   Somatostatin

o   TRH: thyrotropin releasing hormone

·         Pituitary hormones

o   ACTH: adrenocorticotropic hormone

o   αMSH: α-melanocyte stimulating hormone

o   β-endorphin

o   GH: growth hormone

o   PRL: prolactin

o   FSH: follicle stimulating hormone

o   LH: luteinizing hormone

o   TSH: thyrotropin [thyroid stimulating hormone]

·         Opiate peptides

o   β-endorphin

o   Dynorphin

o   Leu-enkephalin

o   Met-enkephalin

·         Neurohypophyseal peptides

o   Oxytocin

o   Vasopressin

·         Neuronal and endocrine peptides

o   ANF: atrial natriuretic peptide

o   CGRP: calcitonin gene-related peptide

o   VIP: vasoactive intestinal peptide

·         Circulating peptides

o   Angiotensin

o   Bradykinin

·         GI and brain peptides

o   CCK: cholecytokinin

o   Gastrin

o   GRP: gastrin releasing peptide

o   Motilin

o   Neurotensin

o   Substance K; substance P (tachykinins)

·         GI and pancreas peptides

o   Glucagon

o   PP: pancreatic polypeptide

·         Neurons only peptides (?)

o   Galanin

o   Neuromedin K

o   NPY: neuropeptide Y

o   PYY: peptide YY

·         Endocrine only peptides (?)

o   Calcitonin

o   Insulin

o   Secretin

o   Parathyroid hormone

·         Frog skin peptides

o   Bombesin

o   Caerulein

o   Ranatensin

(?)  Indicates that the classification approach is still be not certain and my change in the future.

 

A:  Hypothalamic Hormones

The hypothalamus is a region of the brain that contains several types of neurons responsible for secreting different hormones. The hypothalamus is located below the thalamus but just above the brainstem. All vertebrate brains contain a hypothalamus and in humans it is roughly the size of an almond. The hypothalamus is responsible for some metabolic processes and similar activities of the autonomic nervous system and synthesizes and secretes neurohormones or neuropeptides. These types of peptides are often called releasing hormones or hypothalamic hormones which in turn stimulate or inhibit the secretion of pituitary hormones. The hypothalamus controls body temperature, hunger, and important aspects of parenting and attachment behaviors, thirst, fatigue, sleep, and the circadian clock. All of the secreted peptides are released into the blood in the capillaries and travel immediately in portal veins to a second capillary bed in the anterior lobe of the pituitary, where they exert their effects.  Neuropeptides are released in periodic spurts which is why replacement hormone therapy with these hormones does not work unless the replacements are also given in spurts.

Table 1: Peptide hormones and their physiological effects.

 
 

 

Hormone

Physiological Effects

TRH

Thyrotropin-releasing hormone

A tripeptide: pGlu-His-Pro-NH2; C16H22N6O4; M.W.: 362.38

Stimulates the release of thyroid-stimulating hormone (TSH) and prolactin (PRL) when it reaches the anterior lobe of the pituitary.

GnRH

Gonadotropin-releasing hormone; also known as Luteinizing-hormone-releasing hormone (LHRH) and luliberin.

pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 ; M.W: 1,182.32

GnRH secretion at the onset of puberty triggers sexual development, and from then on it is essential for normal sexual physiology in both males and females. In both sexes, its secretion occurs in periodic pulses usually occurring every 1–2 hours.

GHRH

Growth hormone-releasing hormone; also known as growth-hormone-releasing factor (GRF, GHRF), somatoliberin or somatocrinin.

YADAIFTNSY RKVLGQLSAR KLLQDIMSRQ QGESNQERGA RARL-NH2;M.W: 4,540.34

YADAIFTNSY RKVLGQLSAR KLLQDIMSRQ QGESNQERGA RARL-NH2; M.W.: 5,036.66

GHRH is a mixture of two peptides, one containing 40 amino acids, the other 44.

 

GHRH stimulates cells in the anterior lobe of the pituitary to secrete growth hormone (GH) and release by binding to the GHRH Receptor (GHRHR) on cells in the anterior pituitary.

CRH

Corticotropin-releasing hormone (CRH); also known as corticotropin-releasing factor (CRF) or corticoliberin.

CRH is a peptide of 41 amino acids.

 

CRH sheep: 

 

SQEPPISLDL TFHLLREVLE MTKADQLAQQ AHSNRKLLDI A-NH2; M.W.: 4,667.40

 

Rat and human:

SEEPPISLDL TFHLLREVLE MARAEQLAQQ AHSNRKLMEI I-NH2; M.W.: 4,754.50

CRH acts on cells in the anterior lobe of the pituitary to release adrenocorticotropic hormone (ACTH). CRH is also synthesized by the placenta and appears to determine the duration of pregnancy. It may also play a role in keeping the T cells of the mother from mounting an immune attack against the fetus. The portal system carries the CRH to the anterior lobe of the pituitary, where it stimulates corticotropes to secrete adrenocorticotropic hormone (ACTH) and other biologically-active substances (β-endorphin). ACTH stimulates the synthesis of cortisol, glucocorticoids, mineralocorticoids and DHEA. CRH can suppress appetite, increase subjective feelings of anxiety, and perform other functions like boosting attention.

 

Somatostatin

Somatostatin is a mixture of two peptides, one of 14 amino acids, the other of 28.

AGCKNFFWKT FTSC, 14mer; M.W.: 1,636.72

SANSNPAMAP RERKAGCKNF FWKTFTSC, 28mer; M.W.: 3,146.46

Somatostatin acts on the anterior lobe of the pituitary and inhibits the release of growth hormone (GH), and the release of thyroid-stimulating hormone (TSH). Somatostatin is also secreted by cells in the pancreas and in the intestine where it inhibits the secretion of a variety of other hormones.

 

Dopamine

Dopamine is a derivative of the amino acid tyrosine.

In the hypothalamus it inhibits the release of prolactin (PRL) from the anterior lobe of the pituitary.

 

Vasopressin

Vasopressin is a 9mer peptide (Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly; M.W: 1,066.41) also known as arginine vasopressin (AVP) and the antidiuretic hormone (ADH).

Vasopressin acts on the collecting ducts of the kidney to facilitate the reabsorption of water into the blood to reduce the volume of urine formed. Released from the posterior lobe of the pituitary.

 

Oxytocin; 9mer peptide

(Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2; M.W.: 1,006.44).

 

Oxytocin acts on certain smooth muscles and stimulating contractions of the uterus at the time of birth; and stimulating release of milk when the baby begins to suckle. Oxytocin is often given to prospective mothers to hasten birth.

 

 

Table 2: Hypothalamic releasing and inhibiting hormones

Hormone

Target

Physiological Effects

Corticotropin releasing hormone (CRH) is a peptide of 41 amino acids.

 

Anterior lobe of the pituitary

As its name indicates, its acts on cells in the anterior lobe of the pituitary to release adrenocorticotropic hormone (ACTH) and is also synthesized by the placenta and appears to determine the duration of pregnancy.

It is thought to also play a role in keeping the T cells of the mother from mounting an immune attack against the fetus.

Growth hormone releasing hormone (GHRH) is a mixture of two peptides, one containing 40 amino acids, the other 44 amino acids.

Anterior lobe of the pituitary

GHRH stimulates cells in the anterior lobe of the pituitary to secrete growth hormone (GH).

 

Luteinizing hormone releasing hormone (LHRH) Reproductive hormone, also called

gonadotropin-releasing hormone

Anterior pituitary gland

A hormone produced by the hypothalamus that signals the anterior pituitary gland to begin secreting luteinizing hormone and follicle-stimulating hormone. A glycoprotein hormone involved in the regulation of reproductive processes.

Gonadotropin-releasing hormone also known as Luteinizing-hormone-releasing hormone (LHRH) and luliberin.

pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2

Anterior pituitary gland

Release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary.

GnRH activity is very low during childhood, and is activated at puberty or adolescence.

Somatostatin, or growth hormone release inhibiting hormone has two active forms produced by alternative cleavage of a single preproprotein: one of 14 amino acids, the other of 28 amino acids.

Heart

stomach,

acid-producing parietal cells.

Regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.

In the stomach, somatostatin acts on the acid-producing parietal cells via G-coupled receptor to reduce secretion. Somatostatin also indirectly decreases stomach acid production by preventing the release of other hormones, including gastrin, secretin and histamine.

Thyrotropin-releasing hormone (TRH), or thyrotropin-releasing factor (TRF), or thyroliberin or protirelin,

 

Stimulates the release of TSH (thyroid-stimulating hormone) and prolactin from the anterior pituitary.

 

B:  The Pituitary Gland and its Hormones

The pituitary gland is located below the brain in a midline pocket or fossa, a small cavity or depression, of the sphenoid bone. The sphenoid bone is an unpaired cranial bone located at the front in the middle of the skull in front of the temporal bone and basilar part of the occipital bone. The occipital bone is a saucer-shaped membrane bone situated at the back and lower part of the cranium. This depression is also known as the sella turcica. The sella turcica or “Turkish Chair” is a saddle-shaped depression in the sphenoid bone of the human skull and also found in the skulls of other Hominidae, the great ape family of primates, including chimpanzees, orangutans, and gorillas. The human gland is divided into two lobes in which the anterior lobe constitutes two thirds of the volume of the gland and the posterior lobe one third.

The posterior part of the pituitary gland is a protrusion at the bottom of the hypothalamus at the base of the brain. Neurons in the hypothalamus project directly to the posterior pituitary gland and approximately 100 000 axons form the hypophyseal nerve tract. The posterior pituitary gland is formed from axons and nerve terminals of hypothalamic neurons. Electrical excitation releases hormones stored in the terminals. In addition, nerve terminals are surrounded by modified astrocytes known as pituicytes. Different types of pituitary cells produce hormones that are released into the bloodstream which affect other organs in the body. The pituitary gland secretes different types of peptide hormones and is sometimes called the master gland because it controls the functions of many other systems.

 

Table 3: Hormones secreted by the pituitary gland

 

Gland

Neuropeptide

Notes

anterior pituitary

 

Synthesizes and secretes endocrine hormones

Somatotrophins:

Growth hormone

somatostatin

Thyrotrophins:

Thyroid-stimulating hormone

Corticotropins:

Adrenocorticotropic hormone

Beta-endorphin

Lactotrophins

Prolactin

Gonadotropins:

Luteinizing hormone

Follicle-stimulating hormone

Released from the anterior pituitary under the influence of the hypothalamus. Hypothalamic hormones are secreted to the anterior lobe via special capillary system, called the hypothalamic-hypophysial portal system.

 

posterior pituitary

 

Stores and secretes but does not synthesize endocrine hormones

Antidiuretic hormone (ADH, also known as vasopressin and AVP, arginine vasopressin)

 

Oxytocin

Oxytocin creates a positive feedback loop. For example, uterine contractions stimulate the release of oxytocin from the posterior pituitary, which, in turn, increases uterine contractions. This positive feedback loop continues throughout labor.

Intermediate lobe

Synthesizes and secretes endocrine hormone

Melanocyte–stimulating hormones (MSHs)

Sometimes called "intermedins," as these are released by the pars intermedia.

 

 

Table 4:  Targets and effects of hormones secreted by the pituitary gland

Gland

Hormone

Target

Physiological Effects

Anterior Pituitary

Growth hormone

Liver, adipose tissue

Promotes growth (indirectly), control of protein, lipid and carbohydrate metabolism

Anterior Pituitary

Thyroid-stimulating hormone

Thyroid gland

Stimulates secretion of thyroid hormones

Anterior Pituitary

Adrenocorticotropic hormone

Adrenal gland (cortex)

Stimulates secretion of glucocorticoids

Anterior Pituitary

Prolactin

Mammary gland

Milk production

Anterior Pituitary

Luteinizing hormone

Ovary and testis

Control of reproductive function

Anterior Pituitary

Follicle-stimulating hormone

Ovary and testis

Control of reproductive function

Posterior Pituitary

Antidiuretic hormone

Kidney

Conservation of body water

Posterior Pituitary

Oxytocin

Ovary and testis

Stimulates milk ejection and uterine contractions

 

C:  Tachykinins

Tachykinin peptides belong to a large neuropeptide family found in a wide range of species ranging from amphibians to mammals. The name of this peptide family originates from their ability to rapidly induce contraction of gut tissue. The tachykinin family is characterized by a common C-terminal sequence, Phe-X-Gly-Leu-Met-NH2, where X is either an aromatic or an aliphatic amino acid. All tachykinin peptides cause hypotension, contraction of gut and bladder smooth muscle, and secretion of saliva in mammals. The genes that encode precursor proteins called preprotachykinins are differentially spliced to produce different sets of peptides and the precursor proteins are posttranslational processed with the help of proteases to produce smaller peptides. Neurokinins are part of the tachykinin peptide family also includes Neurokinin B, Substance P, Physalaemin, and Eledoisin. Neurokinin A and B were originally isolated from porcine spinal cord. Neurokinins (substance P, neurokinin A, neurokinin B) and the neurokinin receptors - NK1 and NK3 - are largely expressed in the nucleus of the solitary tract (NST), where they are involved in the central regulation of visceral function. Neurokinin A is involved in hematopoietic regulation while Neurokinin B is known for its role as the mediator of pain transmission. Neurokinin A is also very similar in structure to Substance P and produces some of the same biological actions as Substance P.  Neurokinin A is a potent bronchoconstrictor.  In the gut, Neurokinin A is produced by the intrinsic enteric nervous system.

http://www.biosyn.com/catalog-peptides/Tachykinin-Related-Peptide.aspx

 

Table 5: Tachykinin Releted Peptides

Hormone

Target

Physiological Effects

Neurokinin A; Substance K, Neuromedin L,

NKA: HKTDSFVGLM-NH2; FW 1133.32

http://www.biosyn.com/catalog-peptides/Neurokinins.aspx

 

[Ala5, ß - Ala8] - Neurokinin A (4 - 10);

DAFV - (ß - A) - LM - NH2;

Biotin - Neurokinin A;

Biotin - HKTDSFVGLM - NH2;

Neurokinin A (4 - 10); DSFVGLM - NH2; Neurokinin A, Substance K, Neuromedin L,

NKA; HKTDSFVGLM - NH2;

Neurokinin b; Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2

Gut

A ten amino acid peptide synthesized in the neurons. Neurokinin A is a potent bronchoconstrictor.  In the gut, Neurokinin A is produced by the intrinsic enteric nervous system. The neurokinins are a family of neuropeptides which include substance P (SP) and the two structurally related peptides, neurokinin A (NKA) and neurokinin B (NKB). These neurotransmitters appear to play a key role in the regulation of emotions.
These peptides are derived from two preprotachykinin genes - the PPT-A gene encodes the sequences of Substance P, Neurokinin A, and neuropeptide K and the PPT-B gene encodes the sequence of Neurokinin B.

Neuropeptide K

Porcine: H-Asp-Ala-Asp-Ser-Ser-Ile-Glu-Lys-Gln-Val-Ala-Leu-Leu-Lys-Ala-Leu-Tyr-Gly-His-Gly-Gln-Ile-Ser-His-Lys-Arg-His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2 or H-DADSSIEKQVALLKALYGHGQISHKRHKTDSFVGLM-NH2

CNS

The active peptide excite neurons, provokes behaviorial responses, and is a potent vasodilators and secretagogue.

Neuropeptide γ; MLGVFSDTKHRKHSIQGHGYD

 

Neuropeptide-gamma is an N-terminal extended form of neurokinin A (gamma-prepro-tachykinin 72-92).

Substance P; consists of 11 amino acid residues.

ArgProLysProGlnGlnPhePheGlyLeuMet (RPKPQQFFGLM)

http://www.biosyn.com/catalog-peptides/Substance-P-Analogs-and-Fragments.aspx

CNS

Present in the nervous system and gastrointestinal tract, that causes the contraction of smooth muscle and dilation of blood vessels, and that acts as a potent neurotransmitter especially in the transmission of signals from pain receptors.

 

Table 6:  NPY and related peptides

 

Neuropeptide tyrosine (NPY)

 

http://www.biosyn.com/catalog-peptides/Neuropeptide-Y-(NPY)-Analogs-and-Fragments.aspx

 

A 36-amino acid neurotransmitter neuropeptide found in the brain and the autonomic nervous system of humans. The peptide are also found in many other animals with slight sequence variations. The peptide is mainly produced by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue. In the brain it is produced in various locations including the hypothalamus.  It is thought to have several functions such as the increase in food intake and storage of energy as fat, reducing anxiety and stress, reducing pain perception, affecting the circadian rhythm, reducing voluntary alcohol intake, lowering blood pressure and controlling epileptic seizures.

Pancreatic polypeptide

http://www.biosyn.com/catalog-peptides/Pancreatic-Pancreastatin-and-Chromogranin-A-Polyp.aspx

 

A polypeptide secreted by pancreatic polypeptide producing cells in the islets of Langerhans of the pancreas cells in the endocrine pancreas predominantly in the head of the pancreas. It consists of 36 amino acids and has molecular weight about 4200 Da. The peptide self-regulates pancreatic secretion activities both endocrinic and exocrinic. It also has effects on hepatic glycogen levels and gastrointestinal secretions. IN humans, its secretion is increased after a protein meal, fasting, exercise, and acute hypoglycemia and is decreased by somatostatin and intravenous glucose.

Peptide tyrosine-tyrosine (PYY)

 

http://www.biosyn.com/catalog-peptides/peptide-yy-and-related-peptides.aspx

PYY is also known as peptide tyrosine tyrosine or pancreatic peptide YY3-36. The peptide in humans is encoded by the PPY gene. Peptide YY is a short peptide of 36 amino acids which is released by cells in the ileum and colon in response to feeding. It appears to reduce appetite in humans.

  

Table 7:  VIP-glucagon family

Neuropeptide

Remarks

Glucogen-like peptide-1 (GLP-1)

 

Human

His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly

http://www.biosyn.com/catalog-peptides/glucagons-and-glucagon-like-peptides.aspx

A 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon. GLP-1 is released in response to meal intake.

GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. GLP-1 stimulates insulin secretion and inhibits glucagon secretion. GLP-1 also appears to be a physiological regulator of appetite and food intake. It is thought that decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

Peptide histidine isoleucine (PHI)

http://www.biosyn.com/catalog-peptides/vasoactive-vasoactive-intestinal-peptides-vips.aspx

PHI is a porcine peptide present in large quantities in the intestine. It has sequence homologies with VIO, secetin, glucagon and GIP. It appears to induce a reversible net secretion of fluid and electrolytes in the jejunum and ileum and to some extents in the colon and plays a role in the regulation of prolactin in humans.

Pituitary adenylate cyclase activating peptide (PACAP)

http://www.biosyn.com/catalog-peptides/pituitary-adenylate-cyclase-activating-polypeptides-pacap-and-fragments.aspx

PACAP is similar to vasoactive intestinal peptide. It stimulates enterochromaffin-like cells and binds to vasoactive intestinal peptide receptor and to the PACAP receptor. PACAP has been shown to interact with Secretin receptor. The two forms of pituitary adenylate cyclase-activating Polypeptide are PACAP-27 and PACAP-38. PACAP38 (4.5 kDa), was later found to also exist in a COOH-terminally truncated 27–amino acid long-form equivalent to PACAP38 (1–27) and was called PACAP27 (3.0 kDa). In addition, PACAP27 is amidated at its COOH-terminal end. In all tissues examined, PACAP38 is the predominant form of PACAP. The peptide is structurally related to VIP and is therefore a member of the glucagon/VIP family of peptides comprising secretin, helodermin, helospectin, and GLP-1. PACAP27 displays 68% identity with the full length of VIP. The wide distribution of PACAP and its receptors suggests that the peptide may exert pleiotropic physiological functions.

Vasoactive intestinal polypeptide (VIP)

http://www.biosyn.com/catalog-peptides/vasoactive-vasoactive-intestinal-peptides-vips.aspx

 

VIP contains 28 amino acid residues. This neuropeptide belongs to a glucagon/secretin superfamily which are the ligands of class II G protein-coupled receptors. VIP is produced in many tissues of vertebrates including the gut, pancreas and suprachiasmatic nuclei of the hypothalamus in the brain. It stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder. The peptide has a half-life (t½) of about two minutes in the blood.

 

Table 8:  Other peptides

 

Brain natriuretic peptide (BNP)

 

http://www.biosyn.com/catalog-peptides/brain-natriuretic-peptides-bnp.aspx

 

BNP is a 32 amino acid polypeptide that is secreted by the ventricles of the heart in response to stretching of heart muscles. The peptide belongs to the natriuretic family of peptides that contain three structurally related paracrine factors: Atrial, Brain and C-type natruirectic peptides. Both atrial and brain natriuretic peptides are secreted in the atria and ventricles of the heart while C-type peptide is secreted in the bone.  BNP is co-secreted along with a 76 amino acid N-terminal fragment (NT-proBNP) which is biologically inactive. BNP is a horseshoe-shaped 32 amino acid peptide that connected by a disulphide bridge formed between amino acids 10 and 26 and produced by cleavage of the large precursors- prepro and prohormones. BNP activates a transmembrane guanylyl cyclase, natriuretic peptide receptor-A (NPR-A). Activated NPR-A in turn produces the second messenger cGMP that triggers effectors that mediate its cardiac functions. BNP decreases systemic vascular resistance and central venous pressure resulting in a decrease in cardiac output and blood volume

Calcitonin gene-related peptide (CGRP)

(α- and β-form)

 

http://www.biosyn.com/catalog-peptides/calcitonin-gene-related-peptides-cgrp-fragments.aspx

 

CGRP is a 37-amino acid neuropeptide with potent receptor mediated vasodilatory and cardioexcitatory properties. α-CGRP is a 37-amino acid peptide formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11. The less-studied β-CGRP differs in three amino acids (in humans) and is encoded in a separate gene in the same vicinity. It was discovered when alternative processing of RNA transcripts from the calcitonin gene were shown to result in the production of distinct mRNAs encoding CGRP. A human form of CGRP was isolated from thyroid tissue of patients with medullary thyroid carcinoma. CGRP belongs to the regulatory-peptide family that also includes adrenomedullin and amylin. CGRP consists of an amino-terminal disulphide bridge linked loop between amino acids 2 and 7 followed by alpha helix between amino acids 8 and 18 and a poorly defined turn between residues 19 and 21.  The carboxy and amino terminals of CGRP can interact independently with its receptors. CGRP functions by binding to two G-protein coupled receptors, CGRP1 and CGRP2.  One of the major functions of CGRP is vasodilation of cardiac muscles.  In order to achieve this, CGRP first binds to CGRP1 receptor which results in the production of cAMP which in turn activates Protein Kinase A (PKA).  PKA phosphorylates and opens potassium channels that cause relaxation of muscles. CGRP is widely distributed in the central and peripheral nervous systems.  It produces vascular relaxation via binding to CGRP1 receptor and may play a role in controlling blood pressure.  CGRP also protects tissue injury through its vasodilatory functions, influences the activity of inflammatory cells by recruiting more cells at the site of inflammation, plays a role in migraine during painful phases of the disease, and plays a protective role in cardiac tissue.  

Cholecystokinin (CCK)

 

http://www.biosyn.com/catalog-peptides/cholecystokinin-pancreozymin-peptides.aspx

 

CCK, also called pancreozymin, is a peptide hormone found in the small intestine that constitutes the classical gut hormone triad together with gastrin and secretin. CCK is secreted into the blood following ingestion of a meal and plays a critical role in the ingestion, absorption, intestinal motility, satiety signaling, the inhibition of gastric acid secretion and digestion of food. It stimulats the digestion of fat and proteins. CCK is synthesized by I-cells in the mucosal epithelium of the small intestine and secreted in the duodenum, the first segment of the small intestine, where it causes the release of digestive enzymes and bile from the pancreas and gallbladder. It also acts as a hunger suppressant. It is thought that it also plays a major role in inducing drug tolerance to opioids like morphine and heroin, and is partly implicated in experiences of pain hypersensitivity during opioid withdrawal. CCK was discovered in 1928 because of its ability to induce gallbladder contraction. CCK is a neuropeptide that belongs to a family of hormones identified by the number of amino acids, for eg: CCK58 and CCK33. The Prepro-CCK, a115 amino acid peptide, is first cleaved to pro-CCK which in turn results in CCK58, the major processed form of CCK that assumes a helix-turn-helix configuration. CCK binds to CCK receptors on the cell membrane that when activated increase the turnover of phosphatidyl inositol which results in the release of intracellular calcium.  The calcium released causes increased enzyme secretion either directly or through activation of protein kinase C. CCK induces the gall bladder to contract and eject bile into the intestine and stimulates the acinar cells of the pancreas to release water and ions and stimulates the secretion of a juice rich in pancreatic digestive enzymes. It is known to induce growth of the exocrine pancreas and to stimulate insulin secretion. CCK is the most abundant neuropeptide in the human brain where it induces panic attacks that are antagonized by a central cholecystokinin receptor antagonist. ProCCK is expressed in certain neuroendocrine tumors and sarcomas, and the secretion of CCK is impaired in celiac disease and bulimia nervosa.

Galanin (GAL)

 

http://www.biosyn.com/catalog-peptides/galanins-and-galanin-message-associated-peptide-gmap-fragments.aspx

 

GAL is a neuropeptide found in both the central and peripheral nervous systems that is involved in normal growth and development of the nervous system and is critically important for the recovery of nerve function after nerve injury. The mRNA encoding galanin is composed of a 5’ portion encoding a signal sequence, followed by a Lys-Arg cleavage site, then the 29-amino-acid-long galanin peptide followed by Gly-Lys-Arg at the C-terminal containing the amide donor Gly and the cleavage site Lys-Arg. The galanin-encoding portion of the mRNA is followed by 180 bases encoding a 60-amino-acid-long peptide, named the galanin-message-associated peptide (GMAP). Galanin message-associated peptide (GMAP) is a flanking peptide in mammalian preprogalanin located C-terminally of galanin (GAL). GMAP is generally colocalized with galanin in the central nervous system as well as the peripheral nervous system. The peptide was first isolated from porcine intestine in 1983 and was soon later identified in other tissues including the CNS. Subsequently the human galanin gene was cloned in 1988. Human Galanin consists of 30 amino acids, with a free carboxylic acid on the C-terminus, whereas all other known types of galanin are composed of 29 amino acids with a C-terminus amide. Galanin primarily exerts its effects through G-protein coupled receptors and is capable of opening K+ channels and hyperpolarizing neurons, inhibiting adenylate cyclase activity, inhibiting voltage-gated Ca2+ channels, inhibiting phosphoinositide turnover, and regulating the release of dopamine, noradrenaline, acetylcholine, and glutamate. In addition, galanin alters the release of several neurotransmitters in the CNS. Galanin appears to regulate both fat and glucose levels by altering plasma levels of hormones involved in the maintenance of nutrient and body weight homeostasis. The peptide also has modulatory effects on the perception of pain (nociception) and stimulates the release of growth hormone (GH), prolactin and luteinising hormone (LH) from the pituitary. In the periphery, galanin inhibits insulin secretion from pancreatic ß-cells and contracts or relaxes various gastrointestinal smooth muscles.

Islet amyloid polypeptide (IAPP) or amylin

 

http://www.biosyn.com/catalog-peptides/amylin-peptides-and-fragments.aspx

 

IAPP, a 37-amino acid peptide is secreted by beta-islet cells of the pancreas and a major component of the amyloid deposits in persons with type 2 diabetes mellitus. Amylin is constitutively expressed with insulin in response to elevations of plasma glucose. It is cosecreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1. Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.The discovery of amylin as a major component of amyloid deposits happend by two independent groups in 1987. The human amylin has the amino acid sequence KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY, with a disulfide bridge between cysteine residues 2 and 7. The amidated C-terminus and the disulfide bridge are necessary for the full biological activity of amylin. The amino acid sequence of IAPP is 46% and 43% identical to those of the calcitonin gene-related neuropeptides CGRP-2 and CGRP-1. The (20-29) fragment of amylin is critical to the pathogenesis of islet amyloid. IAPP is synthesized, packaged within the golgi apparatus and secreted within the secretory granule by the islet beta cell. It also acts upon the circulatory system by inhibiting the secretion of the atrial natriuretic peptide (ANP) and is also known to increase thirst level which indicating that it has an action within the central nervous system.

Melanin concentrating hormone (MCH)

 

http://www.biosyn.com/catalog-peptides/melanin-concentrating-hormone-antagonist.aspx

 

MCH is a cyclic 19-amino acid orexigenic hypothalamic peptide originally isolated from the pituitary gland of teleost fish and salmon where it controls skin pigmentation. In mammals it is involved in the regulation of feeding behavior, mood, sleep-wake cycle and energy balance. MCH expressing neurons are located within the lateral hypothalamus and zona incerta. Despite this restricted distribution MCH neurons project widely throughout the brain. MCH knockout mice are hypophagic, eat less and are lean. When administered centrally it increases food intake and weight gain. MCH is a hypothalamic neuropeptide that plays a role in the modulation of food intake and mood. Its effects are mediated by two receptors belonging to the super family of G protein coupled receptors (GPCR): MCHR1 (originally SLC-1/ GPR24) and MCH2R (SLT/S643b), the latter is found in primates but not in rodents. The first reported selective, high affinity MCHR1 antagonist, SNAP 7941, had acute antidepressant and anxiolytic like effects in the rat forced swim test (FST) and social interaction tests and the guinea pig maternal separation induced vocalization test. Two new MCHR1 antagonists, ATC0065 and ATC0175, were also shown to have anxiolytic- and antidepressant-like activity in rodents. Many MCH-R1 antagonists have been described during recent years. Many are small molecules. A novel MCH receptor antagonist, T-226296, a (-) enantiomer of N-[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4'-fluoro[1,1'-biphenyl]-4-carboxamide, exhibited high affinity for cloned human and rat MCH receptors (SLC-1) in receptor binding assays (IC50=5.5+/-0.12 nM for human SLC-1; 8.6+/-0.32 nM for rat SLC-1). T-226296 had high selectivity over other receptors, including the second subtype of the MCH receptor, SLT (MCH2), transporters and ion channels. In Chinese hamster ovary (CHO) cells expressing human SLC-1, T-226296 reversed the MCH-mediated inhibition of forskolin-stimulated cAMP accumulation, inhibited MCH-induced intracellular Ca2+ increase, and also inhibited MCH-stimulated arachidonic acid release.The antagonist radioligand [3H]SNAP 7941 exhibit saturable, high affinity specific binding to membranes from PEAKRAPID 293 cells expressing the mouse MCHR1 . Functional antagonism of MCH-evoked [3H]inositol phosphate formation in HEK 293 cells stably expressing the rat MCHR1. SNAP 94847 produced concentration-dependent dextral shifts in the concentration curve to MCH, with a progressive reduction in the maximal response. Results suggest that SNAP 94847 is a novel, high affinity selective antagonist at the MCHR1 with neurogenesis-independent actions in mouse behavioral models that differentiate it from classic anxiolytic and antidepressant drugs. In vitro functional studies showed it to be a high affinity antagonist of MCH-evoked inositol phosphate formation, producing dextral shifts accompanied by a reduction of the maximal effect in the concentration-effect curve to MCH, consistent with an orthosteric-insurmountable antagonist interaction. The effects of MCH1 receptor antagonists in animal models, together with their rapid onset of effect and lack of adverse CNS effects, suggest that they have potential for treatments of depression and anxiety disorders .

Melanocortins

 

(ACTH, α-MSH and others)

 

http://www.biosyn.com/catalog-peptides/msh-and-msh-sequences.aspx

 

Can we rename this to (?):

 

http://www.biosyn.com/catalog-peptides/melanocyte-stimulating-hormone-release-inhibiting-factor-mif-i-and-analogs.aspx

 

 

 

Melanocortins are a group of peptide hormones which include adrenocorticotropic hormone (ACTH) and the different forms of melanocyte-stimulating hormone (MSH) derived from proopiomelanocortin in the pituitary gland. Melanocortins bind to and activate melanocortin receptors. Melanocyte-stimulating hormone (MSH) got its name because of its effect on melanocytes, cells that contain the black pigment, melanin. MSH is produced by an intermediate lobe of the pituitary gland and is involved in the regulation of important physiological functions including food intake, energy homeostasis, modulation of immune responses and photoprotection. MSH was first isolated by the Yale professor Aaron B. Lerner. In 1958 Lerner and his team isolated this hormone, which he called melatonin, in the pineal gland. Using frogs, Lerner and his colleagues found that melatonin could change skin pigmentation, lightening skin colour. The melanocortins include adrenocorticotropic hormone (ACTH), α-MSH, ß-MSH and γ-MSH. α-MSH is the most important melanocortin for pigmentation. α-Melanotropin is a tridecapeptide, Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2, synthesized and secreted by the pars intermedia of the vertebrate pituitary. This peptide hormone is derived from pro-opiomelanocortin, a precursor protein which contains within its structure the sequences of other melanotropic peptides as well as other hormones. Amino acid sequences of ß and γ MSH:

ß-MSH:Ala-Glu-Lys-Lys-Asp-Glu-Gly-Pro-Tyr-Arg-Met-Glu-His-Phe-Arg-Trp-Gly-Ser-Pro-Pro-Lys-Asp

γ-MSH: Tyr-Val-Met-Gly-His-Phe-Arg-Trp-Asp-Arg-Phe-Gly

α-MSH is the physiologically relevant melanotropin secreted by the pituitary and in most vertebrates plays the essential role in adaptive color changes through its action on integumental chromatophores. The initial actions of MSH are mediated at the level of the melanocyte membrane and involve signal transduction from receptor to adenylate cyclase on the intracellular surface of the membrane. This results in elevated cytosolic cyclic AMP levels followed by melanosome dispersion within dermal melanocytes and melanogenesis within epidermal melanocytes. The action of MSH on dermal melanocytes requires calcium for transduction of signal and cyclic AMP production. Structure-function studies of MSH analogues and fragments have provided important insights relative to the structural requirements of the hormone for receptor binding and transduction. Substitution of certain residues within MSH has led to the development of melanotropins that exhibit extraordinary potency and prolonged biological activity. Five G-protein-coupled melanocortin receptors (MC1-MC5) are expressed in mammalian tissues. The melanocortin receptors support diverse physiological functions, including the regulation of hair color, adrenal function, energy homeostasis, feed efficiency, sebaceous gland lipid production and immune and sexual function. The melanocortins ACTH, α-MSH, ß-MSH and γ-MSH are agonist peptide ligands for the melanocortin receptors and these peptides are processed from the pre-prohormone proopiomelanocortin (POMC). Peptide antagonists for the melanocortin MC1, MC3 and MC4 receptors include agouti-related protein (AgRP) and agouti. Diverse lines of evidence, including genetic and pharmacological data obtained in rodents and humans support a role for the melanocortin MC3 and MC4 receptors in the regulation of energy homeostasis. In most vertebrates, its secretion causes a dramatic darkening of the skin of fishes, amphibians, and reptiles. The darkening occurs as granules of melanin spread through the branches of specialized melanocytes called melanophores. α-MSH is responsible for tanning in humans. When ultraviolet light strikes skin cells (keratinocytes), it activates the transcription factor p53. p53 turns on transcription of the gene encoding POMC. Cleavage of the POMC protein produces α-MSH. This is secreted from the cells and stimulates nearby melanocytes, which is a paracrine effect, to synthesize melanin. The melanin is secreted by the melanocytes and taken up by the skin cells.  α-MSH is found in the brain where it acts to suppress appetite. Some cases of extreme obesity have been traced to mutations in the brain receptor for α-MSH. Presumably these people are unable to respond to the appetite-suppressing effect of their α-MSH. MSH is part of the central hub of a series of important physiological effects. MSH controls hypothalamic production of melatonin and endorphins. Without MSH, deficiency creates chronic non-restful sleep and chronic increased perception of pain, respectively. MSH deficiency causes chronic fatigue and chronic pain. MSH also controls many protective effects in the skin, gut and mucus membranes of the nose and lung. It also controls the peripheral release of cytokines and when there isn't enough MSH, the peripheral inflammatory effects are multiplied. MSH also controls pituitary function, with 60% of MSH deficient patients not having enough antidiuretic hormone.

Neuropeptide FF (F8Fa)

 

FLFQPQRF-NH2

 

Similar peptides

 

http://www.biosyn.com/catalog-peptides/morphine-modulating-neuropeptides.aspx

 

http://www.biosyn.com/catalog-peptides/arg-phe-amide-rfamide-related-peptides.aspx

 

 

 

 

 F8Fa is an octapeptide with the amino acid sequence FLFQPQRFamide and is an FMRFamide-like peptide with a certain number of antiopiate properties. Studies have shown that F8Fa specific receptors are present in the rat central nervous system. RIA revealed that the rat neurohypophysis also contains F8Fa immunoreactive (IR) material (230 +/- 49 pg/neural lobe). HPLC profiles revealed several forms of F8Fa IR. Immunogold staining showed that F8Fa IR was restricted to neurosecretory granules in certain axonal and terminal profiles. Double staining of the same ultrathin sections, using anti-F8Fa antiserum and vasopressin or its neurophysin specific antibodies, revealed that F8Fa IR was colocalized with vasopressin. F8Fa IR was not visible in ocytocinergic fibers or terminals. A striking depletion of F8Fa IR (80%) was observed in rats which were given 2% saline to drink for 6 days. Similarly, an IP injection of an hypertonic saline solution was shortly followed by a 20% drop of F8Fa IR. These results suggest that F8Fa IR may act as a paracrine/endocrine mediator released from the rat neurohypophysis.

“Neuropeptide FF (NPFF) and neuropeptide AF (NPAF) are two mammalian amidated neuropeptides which are highly concentrated in the posterior pituitary, spinal cord, hypothalamus and medulla. One precursor protein has been identified in mouse, rat, bovine and human brain. The precursor contains a single copy of both peptides, followed by a glycine residues necessary for amidation and flanked by basic residues necessary for processing by enzymes. In the brain, NPFF-like immunoreactive neurons are found in the hypothalamus and medulla. These systems may be associated with observed effects of NPFF on memory and autonomic regulation, respectively. A hypothalamo-pituitary pathway may be involved in neuroendocrine regulation. This is supported by lack of NPFF in the pituitary gland of vasopressin-deficient Brattleboro rats. It is also possible that NPFF acts as a hormone, as it has been detected in human plasma. The spinal cord contains an intrinsic NPFF-IR neuron system, with cell bodies in the dorsal horn and around the central canal. Nerve terminals are highly concentrated in the superficial laminae of the dorsal horn, where NPFF-immunoreactivity can be released by, e.g., potassium and substance P. One specific high-affinity binding site, distinct from binding sites for other peptides, has been characterized in the rat and human brain and spinal cord. The NPFF receptor appears to be coupled to a G-protein, but details of the second messenger systems have not been clarified yet. Intracerebroventricular injection of NPFF induces a vigorous abstinence syndrome in morphine-tolerant rats. Although clear antiopioid-like effects of NPFF on pain have been observed, some studies have also demonstrated long-lasting analgesic effects. These findings and the observed increase in NPFF-immunoreactivity in the cerebrospinal fluid during development of opiate tolerance render NPFF an interesting and challenging target of investigation.” (Source: Panula P, Aarnisalo AA, Wasowicz K.; Neuropeptide FF, a mammalian neuropeptide with multiple functions. Prog Neurobiol. 1996 Mar-Apr;48(4-5):461-87.

Neurotensin

 

http://www.biosyn.com/catalog-peptides/neurotensin-analogs-and-fragments.aspx

 

Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system. Neurotensin was first isolated from extracts of bovine hypothalamus based on its ability to cause a visible vasodilation in the exposed cutaneous regions of anesthetized rats. Furthermore, neurotensin is distributed throughout the central nervous system, with highest levels in the hypothalamus, amygdala and nucleus accumbens. It induces a variety of effects, including: analgesia, hypothermia and increased locomotor activity. It is also involved in regulation of dopamine pathways. In addition, neurotensin is found in the periphery of endocrine cells of the small intestine where it leads to secretion and smooth muscle contraction. NT belongs to a family of regulatory peptides that also includes neuromedin N (NMN), xenopsin, xenin, and the NT-related hexapeptide LANT-6. in rat. NT was discovered by Carraway and Leeman in 1973. The stimulatory effects of NT and several NT fragments were evaluated by Quirion et al., in 1980, in pharmacological preparations of rat stomach strips and isolated spontaneously beating atria of guinea pigs. Neurotensin (pGlu-L-Y-E-N-K-P-R-R-P-Y-I-L-OH, NT) is a regulatory peptide found in the brain and gut. Both rat stomach strips and cimetidine-treated atria of guinea-pigs were found suitable for studying the relationship between the chemical structure of NT and its myotropic or inotropic activity. Besides their relatively high sensitivity to NT, the two preparations allowed the measurement of at least two complete dose-response curves to NT or its fragments. Using both assays to evaluate the biological activities of NT and NT fragments, the following conclusions were drawn: (a) The minimum structure required to produce the maximum response in the two preparations is H-Arg9-Pro10-Tyr11-Ile12-Leu13-OH; (b) The sequence 1-8 and the amino acids Ile12 and Leu13 contribute mainly to the affinity or binding of NT to its receptors; (c) The sequence 9-11 (Arg9-Pro10-Tyr11) appears to contain the chemical groups responsible for the intrinsic activity or ability of NT to stimulate its receptors. Structure-activity relationship studies by another group have shown that the C-terminal sequence [R-R-P-Y-I-L-OH, NT (8-13)] is sufficient in preserving high affinity receptor binding. Unfortunately, this truncated peptide was found to have poor in vitro and in vivo serum stability. One site of enzymatic instability is the Arg8-Arg9 bond. By replacing one or both of the arginines with a suitable mimic, neurotensin analogs with increased serum stability have been prepared. It was also found that the C-terminal region of the peptide is susceptible to degradation. Cyclic analogues of NT: [cyclo (13----8), Gly8]NT-(8-13), [cyclo (13----7), Gly7]NT-(7-13), [cyclo (13----5 epsilon), Lys5]NT-(5-13), [cyclo (13----4 epsilon), Lys4]NT-(4-13), and their linear precursors have been synthesized by Grinshteine et al., in 1985. The latter (protected linear compounds) were prepared by solid-phase peptide synthesis, and cyclization was attained by using diphenylphosphoryl azide. Cyclization of C-terminal hexa- and octapeptide fragments of NT was found to lead to cycloanalogues possessing high depressor activity. As judged by CD spectral data in aqueous solution, the cyclohexapeptide analogue has a relatively rigid conformation different from its linear counter-part and the NT-(9-13) fragment, whereas NT, its cyclohepta- and cyclononapeptides have random structure. In mammals, NT and related peptides exert their biological effects through three distinct types of receptors termed NT receptor type (NTR) 1, NTR2, and NTR3. NTR1 and NTR2 belong to the family of seven-transmembrane domain G protein-coupled receptors, whereas NTR3 is a single-transmembrane domain non-G protein-coupled receptor. All types of NT receptors are able to bind the C-terminal region of NT, NT8–13, which is the shortest biological active fragment of the peptide. The three NT receptors are expressed in the central nervous system and in peripheral organs. For instance, NTR1 mRNA is expressed in the gastrointestinal tract, NTR2 mRNA is present in the uterus and gastric fundus, and NTR3 mRNA is found in the spinal cord, heart, thyroid, placenta, and testis. NTR are overexpressed in different human tumors, such as human ductal pancreatic adenocarcinoma. New stable neurotensin analogs with high receptor affinity synthesized by replacing arginine residues with lysine and arginine derivatives, were used to explore the biodistribution, tumor uptake, kidney localization, and stability characteristics of these new analogs in order to develop new diagnostic tools for exocrine pancreatic cancer. In addition the N-terminal NT fragment NT1–11 inhibits cortisol secretion, whereas NT, NT1- 8 and NT8–13 are devoid of effect on corticosteroidogenesis. This observation indicated that, besides its intrinsic inhibitory effect, NT1–11 may also modulate the responses of the human adrenal gland to corticotropic factors. It was suggested that NT1–11 itself or synthetic NT1–11 agonists may be of potential interest for the treatment of both Adrenocorticotropic hormone (ACTH) independent and -dependent hypercortisolisms. NT and its active fragment NT (8-13) elicit behavioral responses typical of clinically used antipsychotic drugs when administered directly to the brain. However, limited peptide stability and oral bioavailability have prevented these compounds from being developed as relevant pharmaceuticals. Recently a first-generation NT (8-13) derivative, KK13, was designed. This derivative elicited key pharmacokinetic and behavioral responses typical of clinically used antipsychotic drugs when administered to rats parenterally. This compound was the basis for the rational design of a series of second-generation NT (8-13) analogs (KH1-KH30). Initial screening of these analogs for central nervous system activity by monitoring hypothermia induction after peripheral administration defined several compounds (KH11, KH24, KH26, and KH28-KH30) that warranted further investigation. Each compound maintained binding affinity for NTR (1), however, only KH24, KH26, and KH28 (as well as KK13) elicited significant hypothermic responses after oral administration. Of these, KH28 demonstrated an oral activity 3-fold greater than any other analog; hence it was further characterized in a series of rat behavioral assays. KH28 attenuated d-amphetamine induced hyper-locomotion. In addition, tolerance to the compound did not develop after repeated daily dosing, as measured by hypothermic induction as well as attenuation of d-amphetamine induced hyper-locomotion. Finally, KH28 did not produce catalepsy, a deleterious side-effect elicited by classical antipsychotic drugs. KH28 is considered to be an ideal compound for further development as a potential novel antipsychotic. A brain-penetrating neurotensin analog, NT69L, blocks nicotine-induced locomotor sensitization by blocking both the initiation and the expression of sensitization. In addition, it was reported that a chronic NT69L administration blocked the acute effects of nicotine on norepinephrine and serotonin in prefrontal cortex.

Parathyroid hormone related protein (PTHrP)

TRSAW

 

http://www.biosyn.com/catalog-peptides/pTH-Related-Protein-Sequences.aspx

 

Can this be changed to (?):

 

http://www.biosyn.com/catalog-peptides/Parathyroid-homonr-related-protein.aspx

PTHrP is a member of the parathyroid hormone family that is occasionally secreted by cancer cells (breast cancer, certain types of lung cancer including squamous cell lung carcinoma) besides its normal functions. Parathyroid hormone–related peptide (PTHrP), a peptide hormone derived from normal and tumor cells is a naturally occurring angiogenesis inhibitor that regulates bone metabolism and vascular tone. PTHrP was discovered in association with certain types of cancer that caused elevated blood Ca2+ levels (a syndrome called humoral hypercalcemia of malignancy, or HHM) in affected patients. The mature PTHrP of teleost fish is 161 amino acids long. Regions with high sequence conservation across all the vertebrates, including 22 of the first 34 amino acids, suggest they interact with the common PTH/PTHrP receptors. Other regions of high conservation are 11 of the 18 amino acids of the Arg-rich RNA binding region and 7 of the 15 amino acids of the nuclear localization sequence. Comparison of the COOH-terminal region of PTHrPs revealed that it is much shorter in fish than in tetrapods. PTHrP appears to modulate cell proliferation and differentiation in both the pre and post natal period. PTH/PTHrP receptor expression in the mouse is controlled by two promoters. Furthermore, it was found that, while the downstream promoter controls PTH/PTHrP receptor gene expression in bone and cartilage, it is differentially regulated in the two tissues. 1-alpha, 25-dihydroxyvitamin D3 downregulated the activity of the downstream promoter in osteoblasts, but not in chondrocytes, both in vivo and in vitro. Most of the biological activity of PTHrP is thought to be mediated by binding of its amino terminus to the PTH/PTHrP receptor. However, recent evidence suggests that amino acids 87-107, outside of the amino terminal binding domain, act as a nucleolar targeting signal. PTHrP appears to act as a bifunctional modulator of both chondrocyte proliferation and differentiation, through signal transduction linked to the PTH/PTHrP receptor and by its direct action in the nucleolus. Furthermore human platelets express PTH1R. PTHrP can interact with this receptor to enhance human platelet activation induced by