RVD-Hpα

RVD-Hpα fragment of hemoglobin (pepcan-12), alpha 1
File:RVD-hemopressin structure.png A polypeptide fragment derived from residues 92-104 (RVDPVNFKLLSH) in the human sequence
Identifiers
Symbol	HBA1
CAS number	1193362-76-3
NCBI gene	3039
HGNC	4823
OMIM	141800
RefSeq	NM_000558
UniProt	P69905
Other data
Locus	Chr. 16 p13.3
Search for Structures Swiss-model Domains InterPro

RVD-Hpα (also known as RVD-hemopressin or Pepcan-12) is an endogenous neuropeptide found in human and mammalian brain, which was originally proposed to act as a selective agonist for the CB₁ cannabinoid receptor. It is a 12-amino acid polypeptide having the amino acid sequence Arg-Val-Asp-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal extended form of hemopressin, a 9-AA polypeptide derived from the α₁ subunit of hemoglobin which has previously been shown to act as a CB₁ inverse agonist. All three polypeptides have been isolated from various mammalian species, with RVD-Hpα being one of the more abundant neuropeptides expressed in mouse brain, and these neuropeptides represent a new avenue for cannabinoid research distinct from the previously known endogenous lipid-derived cannabinoid agonists such as anandamide. Recently it was shown that RVD-Hpα (also called Pepcan-12) is a potent negative allosteric modulator at CB₁ receptors, together with other newly described N-terminally extended peptides (pepcans). However other research suggests that RVD-hemopressin may sometimes act as a positive allosteric modulator of CB₁ in certain tissues or under certain conditions, and its effects can be blocked by CB₁ antagonists. RVD-hemopressin has also been shown to block the TRPV1 channel, which is a target shared with other endocannabinoid ligands such as anandamide and N-Arachidonoyl dopamine.

Pepcan-12 is the major peptide of a family of endogenous peptide endocannabinoids (pepcans) shown to act as negative allosteric modulators (NAM) of cannabinoid CB₁ receptors. It has more recently been discovered that pepcan-12 also acts as a potent CB₂ cannabinoid receptor positive allosteric modulator (PAM), thus reducing CB₁ mediated signalling while simultaneously increasing signalling mediated by CB₂. This peptide is specifically expressed in the noradrenergic neurons in the brain, mainly the locus coeruleus and its projections and in the adrenal medulla. As a positive allosteric modulator of CB₂, RVD-Hpα has been shown to significantly potentiate the effects of CB₂ receptor agonists, including the endocannabinoid 2-arachidonoyl glycerol (2-AG), for GTPγS binding and cAMP inhibition (5–10 fold). The precursor pepcan-23 was identified with pepcan-12 in brain, liver and kidney in mice, and is cleaved to release pepcan-12. RVD-Hpα was increased upon endotoxemia and ischemia reperfusion damage where CB₂ receptors play a protective role. The wide occurrence of this endogenous hormone-like CB₂ receptor PAM, with unforeseen opposite allosteric effects on cannabinoid receptors, suggests its potential role in peripheral pathophysiological processes.

In contrast to RVD-Hpα which produces antagonist or inverse agonist activity at CB₁ under most conditions but acts as an agonist at CB₂, the shorter 11-amino acid peptide fragment VD-Hpα produces agonist effects at CB₁ but has little or no activity at CB₂, producing centrally mediated analgesic effects, hypothermia and increased sleep in animal studies through activation of the CB₁ receptor. Hybrid peptides combining VD-Hpα with peptide agonists for neuropeptide VF and opioid receptors have also been developed to produce dual acting compounds.

species	RVD-Hpα sequence
human	RVDPVNFKLLSH
mouse	RVDPVNFKLLSH
rat	RVDPVNFKfLSH
consensus	RVDPVNFKxLSH