Affiliation:
1. From the Centre for Cardiovascular Biology and Medicine, King’s College London, London, UK.
Abstract
Abstract
—Activation of the sarcolemmal Na
+
-H
+
exchanger (NHE) has been implicated as a mechanism of inotropic, arrhythmogenic, antiacidotic, and hypertrophic effects of α
1
-adrenoceptor (AR) stimulation. Although such regulation of sarcolemmal NHE activity has been shown to be selectively mediated through the α
1A
-AR subtype, distal signaling mechanisms remain poorly defined. We investigated the roles of various kinase pathways in α
1A
-AR–mediated stimulation of sarcolemmal NHE activity in adult rat ventricular myocytes. As an index of NHE activity,
trans
-sarcolemmal acid efflux rate (
J
H
) 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
rsk
activities were indexed on the basis of analysis of their phosphorylation status. In control cells, there was no change in
J
H
in response to vehicle. Phenylephrine and A61603, an α
1A
-AR subtype–selective agonist, increased
J
H
, as well as cellular ERK and p90
rsk
activities. Neither agonist affected p38 activity, which was increased with sorbitol. The MAPK kinase inhibitor PD98059 abolished phenylephrine- and A61603-induced increases in
J
H
and cellular ERK and p90
rsk
activities. In contrast, the PKC inhibitor GF109203X abolished phenylephrine- and A61603-induced increases in
J
H
but failed to prevent the increases in ERK and p90
rsk
activities. Our findings suggest that α
1A
-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
rsk
. Activation of PKC is also required for α
1A
-AR–mediated NHE stimulation, but such regulation occurs through an ERK-independent pathway.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
96 articles.
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