Homologous desensitization of calcitonin gene-related peptide response in rat glomerular mesangial cells in culture

Abstract

Addition of calcitonin gene-related peptide (CGRP) to rat glomerular mesangial cells in culture resulted in an increase in cyclic adenosine monophosphate (cAMP) accumulation in a concentration-dependent fashion with an EC50 of approximately 3 nM. Inclusion of CGRP8-37, a CGRP1 selective antagonist shifted CGRP concentration-response curve to the right, suggesting the presence of CGRP1 subtype receptors in these cells. Pretreatment of these cells with CGRP followed by washing and rechallenge with CGRP or isoproterenol or forskolin resulted in selective attenuation of CGRP-mediated cAMP accumulation by 55-60% without affecting isoproterenol or forskolin-mediated accumulation, suggesting that CGRP pretreatment of mesangial cells induced homologous desensitization. CGRP-mediated desensitization of cAMP accumulation was found to be both concentration- and time-dependent. Desensitization did not affect the EC50 of CGRP for stimulation of cAMP accumulation, but resulted in a 55-60% reduction in maximal response. CGRP-mediated desensitization was fast, with half-maximal desensitization occurring as early as 5 min after pretreatment with CGRP. In addition, CGRP-mediated desensitization was blocked by the CGRP receptor antagonist, CGRP8-37, when included in the pretreatment protocol. These data suggest that rat mesangial cells display CGRP1 subtype receptors and that prolonged pretreatment of these cells with CGRP resulted in homologous desensitization.

Rat-2 fibroblasts express specific adrenomedullin receptors, but not calcitonin-gene-related-peptide receptors, which mediate increased intracellular cAMP and inhibit mitogen-activated protein kinase activity

“…This agrees with published findings showing that adrenomedullin decreases PDGF-stimulated MAPK activity in mesangial cells [27]. However, mesangial cells express CGRP receptors [48] and, as adrenomedullin is capable of acting via CGRP receptors to increase cAMP [17], this cannot be discounted as a mechanism in mesangial cells. In support of this hypothesis, CGRP is able to inhibit thymocyte [49] and splenocyte [50] cell growth.…”

Tonic activation of A2A adenosine receptors unmasks, and of A1 receptors prevents, a facilitatory action of calcitonin gene‐related peptide in the rat hippocampus

“…To minimise underestimation of the CGRP responses due to desensitization (see Aiyar et al ., 1992), only one concentration of CGRP was applied to each slice, and thus, the concentration response curves showed in this paper were performed in a non‐cumulative manner. CGRP was applied to each slice either alone or in the presence of adenosine receptor agonists and/or antagonists.…”

Receptors mediating CGRP‐induced relaxation in the rat isolated thoracic aorta and porcine isolated coronary artery differentiated by hα CGRP8–37

“…vas deferens) and seven (e.g. pulmonary artery) might match a CGRP 2 and a CGRP 1 receptor, respectively, but there are several values at least an order of magnitude higher than that at the pulmonary artery CGRP 1 receptor (Chin et al ., 1994; Entzeroth et al , 1995; Bell & McDermott, 1994; Aiyar et al ., 1992; Poyner et al ., 1992). This range of hα CGRP 8–37 affinities has been obtained from rat in vitro and perfused tissues, and isolated cells.…”