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Biotech / Medical : Indications -- obesity/erectile dysfunction

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From: scaram(o)uche8/28/2017 3:33:29 PM
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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.

1
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012, Bern, Switzerland.
2
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
3
Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
4
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012, Bern, Switzerland. gertsch@ibmm.unibe.ch.

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
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