© 2000 American Heart Association, Inc.
Cellular Biology |
Roles of Mitogen-Activated Protein Kinases and Protein Kinase C in 
1A-Adrenoceptor–Mediated Stimulation of the Sarcolemmal Na+-H+ Exchanger
From the Centre for Cardiovascular Biology and Medicine, King’s College London, London, UK.
Correspondence to Dr Metin Avkiran, Cardiovascular Research, The Rayne Institute, St Thomas’ Hospital, London SE1 7EH, UK. E-mail metin.avkiran{at}kcl.ac.uk
Abstract—Activation of the
sarcolemmal Na+-H+ exchanger (NHE) has been
implicated as a mechanism of inotropic, arrhythmogenic, antiacidotic,
and hypertrophic effects of 
1-adrenoceptor (AR)
stimulation. Although such regulation of sarcolemmal NHE activity has
been shown to be selectively mediated through the 1A-AR
subtype, distal signaling mechanisms remain poorly defined. We
investigated the roles of various kinase pathways in
1A-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 p90rsk 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 1A-AR
subtype–selective agonist, increased JH, as
well as cellular ERK and p90rsk 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 p90rsk
activities. In contrast, the PKC inhibitor GF109203X
abolished phenylephrine- and A61603-induced increases in
JH but failed to prevent the increases in
ERK and p90rsk activities. Our findings suggest that
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 p90rsk. Activation of PKC is also
required for 1A-AR–mediated NHE stimulation, but such
regulation occurs through an ERK-independent pathway.
Key Words: Na+-H+ exchange • receptors, adrenergic • signal transduction • protein kinases
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