|Sci Rep. 2017 Aug 25;7(1):9560. doi: 10.1038/s41598-017-09808-8.|
Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage.
Petrucci V1,2, Chicca A1, Glasmacher S1, Paloczi J3, Cao Z3, Pacher P3, Gertsch J4.
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012, Bern, Switzerland.
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012, Bern, Switzerland. email@example.com.
Pepcan-12 (RVD-hemopressin; RVDPVNFKLLSH) is the major peptide of a family of endogenous peptide endocannabinoids (pepcans) shown to act as negative allosteric modulators (NAM) of cannabinoid CB1 receptors. Noradrenergic neurons have been identified to be a specific site of pepcan production. However, it remains unknown whether pepcans occur in the periphery and interact with peripheral CB2 cannabinoid receptors. Here, it is shown that pepcan-12 acts as a potent (K i value ~50?nM) hCB2 receptor positive allosteric modulator (PAM). It significantly potentiated the effects of CB2 receptor agonists, including the endocannabinoid 2-arachidonoyl glycerol (2-AG), for [35S]GTP?S binding and cAMP inhibition (5-10 fold). In mice, the putative precursor pepcan-23 (SALSDLHAHKLRVDPVNFKLLSH) was identified with pepcan-12 in brain, liver and kidney. Pepcan-12 was increased upon endotoxemia and ischemia reperfusion damage where CB2 receptors play a protective role. The adrenals are a major endocrine site of production/secretion of constitutive pepcan-12, as shown by its marked loss after adrenalectomy. However, upon I/R damage pepcan-12 was strongly increased in the liver (from ~100 pmol/g to ~500 pmol/g) independent of adrenals. 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