Roles of Mitogen-Activated Protein Kinases and Protein Kinase C in α1A-Adrenoceptor–Mediated Stimulation of the Sarcolemmal Na+-H+ Exchanger

• Published in: Circulation research 2000-02, Vol.86 (2), p.214-220
• Main Authors: Snabaitis, Andrew K, Yokoyama, Hiroyuki, Avkiran, Metin
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Heart; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571

ABSTRACTActivation of the sarcolemmal Na-H exchanger (NHE) has been implicated as a mechanism of inotropic, arrhythmogenic, antiacidotic, and hypertrophic effects of α1-adrenoceptor (AR) stimulation. Although such regulation of sarcolemmal NHE activity has been shown to be selectively mediated through the α1A-AR subtype, distal signaling mechanisms remain poorly defined. We investigated the roles of various kinase pathways in α1A-AR–mediated stimulation of sarcolemmal NHE activity in adult rat ventricular myocytes. As an index of NHE activity, trans-sarcolemmal acid efflux rate (JH) was determined through microepifluorescence in single cells, during recovery from intracellular acidosis in bicarbonate-free conditions. Extracellular signal-regulated kinase (ERK), p38-mitogen-activated protein kinase (MAPK), and p90 activities were indexed on the basis of analysis of their phosphorylation status. In control cells, there was no change in JH in response to vehicle. Phenylephrine and A61603, an α1A-AR subtype–selective agonist, increased JH, as well as cellular ERK and p90 activities. Neither agonist affected p38 activity, which was increased with sorbitol. The MAPK kinase inhibitor PD98059 abolished phenylephrine- and A61603-induced increases in JH and cellular ERK and p90 activities. In contrast, the PKC inhibitor GF109203X abolished phenylephrine- and A61603-induced increases in JH but failed to prevent the increases in ERK and p90 activities. Our findings suggest that α1A-AR–mediated stimulation of sarcolemmal NHE activity in rat ventricular myocytes requires activation of the ERK (but not the p38) pathway of the MAPK cascade and that the ERK-mediated effect may occur via p90. Activation of PKC is also required for α1A-AR–mediated NHE stimulation, but such regulation occurs through an ERK-independent pathway.