Calcitonin gene-related peptide- and adrenomedullin-induced facilitation of calcium current by different signal pathways in nucleus tractus solitarius

Abstract: Calcitonin gene-related peptides (CGRP) and adrenomedullin (ADM) belong to the calcitonin family of peptides and are structurally related. Both peptides are found in the neurons of the CNS and play a role in many neuronal functions, including the control of blood pressure. The nucleus tractus solitarius (NTS) is known to play a major role in the regulation of cardiovascular, respiratory, gustatory, hepatic and swallowing functions. Recently, hypotension and bradycardia were observed after CGRP and ADM injection in the NTS. Voltage-dependent Ca2+ channels (VDCCs) serve as crucial mediators of membrane excitability and Ca2+-dependent functions, such as neurotransmitter release, enzyme activity, and gene expression. The purpose of this study is to investigate the effects of CGRP and ADM on VDCC currents (I Ca) carried by Ba2+ (I Ba) in the NTS, using patch-clamp recording methods. Application of CGRP and ADM caused facilitation of I Ba in a concentration-dependent manner. Intracellular dialysis of the anti-Gαs-protein antibody attenuated CGRP-induced facilitation of I Ba. Intracellular dialysis of the anti-Gαi-protein antibody attenuated ADM-induced facilitation of I Ba. Pretreatment with SQ22536 (an adenylate cyclase inhibitor) and intracellular dialysis of PKI(5–24) (a protein kinase A inhibitor) attenuated CGRP-induced facilitation of I Ba. In contrast, pretreatment with PD98,059 (a mitogen-activated protein kinas inhibitor) attenuated ADM-induced facilitation of I Ba. Mainly L-type VDCCs were facilitated by both CGRP and ADM. These results indicate that CGRP facilitates L-type VDCCs via Gαs-protein involving adenylate cyclase and protein kinase A. In contrast, ADM facilitates L-type VDCCs via Gαi-protein involving mitogen-activated protein kinase in the NTS. [Copyright &y& Elsevier]