The well-studied hydra peptides are hydra head activator (HHA) peptide and their analogs. The HHA is involved in head-specific growth and differentiation processes in the freshwater coelenterate, Hydra attenuata. It is also present in high concentrations of mammalian (human and bovine) hypothalamus and intestine.
Head activator (7-11) is fragments of the head activator have been used to develop an enzyme-linked immunosorbent assay (ELISA). Sequence of Head activator (7-11) is H-Lys-Val-Ile-Leu-Phe-OH1.
Head activor (HA) was originally isolated and sequenced from two main mammalian sources, hypothalamus and intestine. Using immunological assays in combination with reversephase high-pressure liquid chromatography Schaller HC et al., discovered HA in insects, amphibia, birds and crustaceans2.
HA is a peptide consisting of 11 amino acids. It is a small hydrophilic molecule of < 500 daltons. The structure of the HHA neuropeptide studied using NMR, CD, and Raman spectroscopy and determined to contain 62-67% anti-parallel beta-pleated sheet, and predicted to assume a beta-turn near the amino terminus. Consistent with the secondary structure prediction, an anti-parallel beta-pleated sheet topology was evident from the serine amino acid to the carboxyl terminus. Additionally, a beta-turn occurred near the amino carboxyl terminus. Results indicate that fluctuations occurring at both termini may serve to stabilize the structure ultimately allowing the amino terminus access to its receptor protein3. Bradykinin, which has some amino acid sequence homology with HHA, is an inactive neurotrophic factor4. The sequence of the HA is conserved throughout the animal kingdom.
Mode of Action
The HHA which is a neuropeptides that is released upon injury, is a signaling molecule. It induces cellular differentiation or determination, HA behaves as an agonist of the cyclic AMP (cAMP) pathway involving the modulation of CREB nuclear transcription factor activity. This cascade would be required for proper regeneration, regardless of whether the polarity involved is apical or basal. Modulations of the protein kinase C pathway, which have been shown to affect apical or basal positional values, might signal to bring about this polarity5. HHA is produced by nerve cells and released into the intercellular space bound to large-molecular-weight carrier(s). By additional interaction with extracellular matrix components and self inactivation by dimerisation, a local action is ensured. HHA acts as a mitogen on all dividing cell types in hydra forcing them to pass through G2, divide, and either start a new round of cell division or terminally differentiate. . In mammals, HA is produced by nerve or endocrine cells and it probably acts on nerve-precursor cells. On the neural cell line NH15-CA2 and on the pituitary cell line AtT20, HA acts as mitogen by stimulating cells arrested in G2 to enter mitosis. The presence of HA early in neural development and in abnormal neural development, such as in brain and neuroendocrine tumors, are consistent with a function in growth control for HA in mammals6.
The neuropeptide head activator plays an important role for proliferation and determination of stem cells in hydra 7. At the cellular level HA exerts three types of effects in hydra. It stimulates cells to divide, and it is responsible for the determination and the final differentiation of nerve cells and head-specific epithelial cells. For nerve-cell differentiation the cAMP pathway is used as second messenger system. Components of this pathway were identified in hydra. In mammals head activator is produced by nerve and neuro-endocrine cells, and it acts as mitogen on cells of neural origin. It is present early in neural development and in abnormal neural development, such as brain and neuroendocrine tumours 8. The neuropeptide head activator affects cellular growth and head-specific cellular differentiation during head regeneration and budding9. HA peptide may act as a neurotrophic factor for neurons in mammals10.
1. Schaller HC, Bodenmüller H, Zachmann B, Schilling E (1984). Enzyme-linked immunosorbent assay for the neuropeptide 'head activator'. Eur J Biochem., 138(2):365-371.
2. Schaller HC, Hoffmeister SA, Dübel S (1989). Role of the neuropeptide head activator for growth and development in hydra and mammals. Development,107:99-107.
3. Fuentes EJ, Pachter R, Tsonis PA (1994). On the three-dimensional structure of the Hydra head activator neuropeptide. In Vivo, 8(2):199-205.
4. Quach TT, Duchemin AM, Oliver AP, Schrier BK, Wyatt RJ (1992). Hydra head activator peptide has trophic activity for eukaryotic neurons. Brain Res Dev Brain Res., 68(1):97-102.
5. Galliot B (1997). Signaling molecules in regenerating hydra. Bioessays, 19(1):37-46.
6. Schaller HC, Hoffmeister SA, Dübel S (1989). Role of the neuropeptide head activator for growth and development in hydra and mammals. Development, 107:99-107.
7. Hampe W, Urny J, Franke I, Hoffmeister-Ullerich SA, Herrmann D, Petersen CM, Lohmann J, Schaller HC (1999). A head-activator binding protein is present in hydra in a soluble and a membrane-anchored form. Development, 126(18):4077-4086.
8. Schaller HC, Hermans-Borgmeyer I, Hoffmeister SA (1996). Neuronal control of development in hydra. Int J Dev Biol., 40(1):339-44.
9. Galliot B, Welschof M, Schuckert O, Hoffmeister S, Schaller HC (1995). The cAMP response element binding protein is involved in hydra regeneration. Development, 121(4):1205-1216.
10. Quach TT, Duchemin AM, Oliver AP, Schrier BK, Wyatt RJ (1992). Hydra head activator peptide has trophic activity for eukaryotic neurons. Brain Res Dev Brain Res., 68(1):97-102.
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