Structure-Activity Relationship of Calcitonin Gene-Related Peptide and its Receptor

Abstract

Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide, which is widely distributed in the brain and peripheral nervous system. It possesses a wide variety of biological effects in the brain as well as in peripheral tissues including most potent vasodilator actions, pro-inflammatory and nociceptive effects. The various actions are thought to be due to the stimulation of different CGRP receptors. Thus, the discrimination between CGRP receptor subtypes is most important for clinical therapy. Recently, CGRP receptors have briefly been divided into two subtypes, CGRP1 and CGRP2. However, questions still remain about the extent of the receptor diversity. Structure-activity studies can help to understand how the peptide interacts with receptor. Within the peptide, residues 8-18, especially positively charged arginines at position 11 and 18 are of interest. Most potent CGRP analogues all have those two amino acids. When replaced by the negatively charged glutamic acid, the peptide fragment [11Glu]CGRP8-37 showed weak antagonist activity, while [18GluJCGRP8-37 failed to block the action of CGRP. Fragment fant 18Ser]CGRP8-37 where two hydroxyl side-chain containing serines replaced arginine at position 11 and 18 showed weak antagonist ability at the high concentration of 10µM. Those results revealed that 11 arginine may interact with a hydrophilic partner, while 18 arginine may bind with a negatively charged one. # The exact nature of the CGRP receptors remains uncertain. Nevertheless, Calcitonin Receptor-Like Receptor (CRLR) combined with Receptor Activity- Modified Protein (RAMP’) seems most likely to be a CGRP receptor. Experiments have been carried out to modify the receptor. Glycosylation seems to be important to allow CGRP producing cAMP. The roles of sulphydryl groups are complicated. Their apparent alkylation by NEM reduces cAMP production but increases CGRP binding.