Delta Sleep Inducing Peptide (DSIP)

By Klaus D. Linse

Delta sleep inducing peptide, or DSIP, is a nonapeptide with the sequence WAGGDASGE and a molecular weight of 849 dalton. The peptide was discovered by G. Schoeneberger and M. Monnier in 1974. Results from different research groups indicated that DSIP plays an important role in stress-resistance since DSIP showed stress-protective, antiseizure, and immunomodulating effects. Furthermore, it has been found to also play a role in slowing down the aging process. The peptide mainly induces delta-sleep in rabbits, rats, mice, and humans. However, in cats, the effect on REM sleep was found to be more pronounced. Using radio immune assays (RIA) and immunohistochemistry it was possible for researchers to localize DSIP-like material in the brain and in peripheral organs of the rat as well as in the plasma of several mammals. In addition, the peptide has also been observed to affect electrophysiological activity, neurotransmitter levels in the brain, circadian and locomotor patterns, hormonal levels, psychological performance, and the activity of neuro-pharmacological drugs including their withdrawal. DSIP influences the nocturnal rise of N-acetyltransferase (NAT) activity in the rat pineal gland. The peptide is now known to have multifunctional regulatory properties and numerous studies have confirmed its stress-protective and adaptive activity. Apparently the exact biochemical origin of this peptide is not well known, however, in humans, the sequence is present in the Jumonji domain-containing protein 1B or JMJD1B protein, in lysine-specific demethylase 3B, and the KIAA1082 protein as can be revealed by a BLAST search of the human genome. The JMJD1B protein, encoded by JMJD1B gene, is a ubiquitous protein demethylase that specifically demethylates Lys-9 of histone H3. The protein appears to play a central role in histone regulation. The demethylation of Lys residue generates formaldehyde and succinate. In addition this protein may have tumor suppressor activity. The KIAA1082 protein belongs to a protein domain family that is part of the cupin metallo-enzyme superfamily, smart00558, which includes a JmjC domain encoded by the KIAA1082 gene. This neuropeptide when infused into the mesodiencephalic ventricle of recipient rabbits induces spindle and delta electro-encephalography (EEG) activity and reduced motor activities. Electroencephalography (EEG) refers to the recording of electrical activity along the scalp and measures voltage fluctuations resulting from ionic current flows within the neurons of the brain.

Another peptide called “delta sleep-inducing immunoreactive peptide (DIP)” is a 77-residue NH2-terminally acetylated peptide that was originally isolated from porcine brain (pDIP) using polyclonal antibodies against the delta sleep-inducing peptide (DSIP). As reported by Seidel et al in 1997 pDIP was detected via DSIP-specific antibodies. It is thought that these antibodies may have recognized the sequence GGDA in DSIP and GGSA in pDIP. However the peptide is otherwise not sequence-related to this supposed sleep-inducing peptide. The pDIP sequence contains a putative leucine-zipper motif, a Pro/Glu rich domain, and three potential phosphorylation sites. The human analog of pDIP as characterized by cDNA analysis showed that human DIP (hDIP) differs from the porcine protein in only four residues. Specifically, Arg55 of pDIP is changed to a cysteine in hDIP. Furthermore, hDIP was shown to be present in a large number of tissues by reverse transcription polymerase chain reaction/Southern hybridization analysis.

The TSC22 domain family protein 3 isoform 3 found in humans, also called “delta sleep inducing peptide, immunoreactor” is a TSC-22 related protein. The amino acid sequence is also present in the DSIP-immunoreactive leucine zipper protein and the glucocorticoid-induced leucine zipper protein. These peptides and proteins belong to the TSC22 domain protein family 3. Other names referred to in databases are TSC-22-like protein, TSC-22-related protein, DSIP-immunoreactive peptide, and delta sleep-inducing peptide immunoreactor. The calculated molecular weight is 8,542 dalton. The protein encoded by this gene shares significant sequence identity with the murine TSC-22 and Drosophila shs gene product. Both proteins are leucine zipper proteins that function as transcriptional regulators. The expression of this gene is stimulated by glucocorticoids and interleukin 10. It appears to play a key role in the anti-inflammatory and immunosuppressive effects of this steroid and chemokine and transcript variants encoding different isoforms have also been identified for this gene. [Source RefSeq, Jul 2008].

Delta-Sleep Inducing Peptides (DSIP) and Analogs

 

 

Structural models of the Delta-Sleep Inducing Peptide (DSIP) and Analogs

 

Delta-Sleep Inducing Peptide (DSIP)

 

Chemical structure of DSIP

Energy minimized Van-der-Waals model of DSIP using a simple force field modeling approach.

 

(Asn⁵)-Delta-Sleep Inducing Peptide

 
((Asn5)-Delta-Sleep Inducing Peptide (rabbit); (Asn5)-DSIP (rabbit))

Chemical structure of (Asn⁵)-DSIP

Energy minimized Van-der-Waals model of (Asn⁵)-DSIP using a simple force field modeling approach.

 

(β-Asp⁵)-Delta-Sleep Inducing Peptide

 

H-Trp-Ala-Gly-Gly-Asp(Ala-Ser-Gly-Glu-OH)-OH

 


(β-Asp⁵)-DSIP: Energy minimized Van-der-Waals model using a simple force field modeling approach.

 

This peptide analog is a good substrate for protein L-isoaspartyl methyltransferase, an enzyme found in the brain which is involved in the repair of age-damaged proteins containing atypical iosaspartyl peptide bonds.

 

Porcine Delta-Sleep-Inducing Peptide Immunoreactive Peptide (pDIP)

 

The solution structure for this peptide was determined by Seidel et al. in 1997.

pDIP: Representation of the three-dimensional model of pDIP (Seidel et al 1997).

 

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