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J. Cell Biol.,
Volume 141, Number 7, June 29, 1998 1637-1646
* Institut National de la Santé et de la Recherche Médicale U-390, Laboratoire de Physiopathologie Cardiovasculaire, C.H.U.
Arnaud de Villeneuve, and The Anion Cl Centre National de Recherche Scientifique, Faculté de Pharmacie, 34295 Montpellier Cedex, France
/HCO3 Exchangers AE1,
AE2, and AE3 are membrane pH regulatory ion transporters ubiquitously expressed in vertebrate tissues.
Besides relieving intracellular alkaline and CO2 loads, the AEs have an important function during development and cell death and play a central role in such cellular properties as cell shape, metabolism, and contractility. The activity of AE(s) are regulated by
neurohormones. However, little is known as to the intracellular signal transduction pathways that underlie
this modulation. We show here that, in cardiomyocytes
that express both AE1 and AE3, the purinergic agonist,
ATP, triggers activation of anion exchange. The AE activation is observed in cells in which AE3 expression
was blocked but not in cells microinjected with neutralizing anti-AE1 antibodies. ATP induces tyrosine phosphorylation of AE1, activation of the tyrosine kinase
Fyn, and association of both Fyn and FAK with AE1.
Inhibition of Src family kinases in vivo by genistein,
herbimycin A, or ST638 prevents purinergic activation
of AE1. Microinjection of either anti-Cst.1 antibody or
recombinant CSK, both of which prevent activation of
Src family kinase, significantly decreases ATP-induced
activation of AE. Microinjection of an anti-FAK antibody as well as expression in cardiomyocytes of Phe397
FAK dominant negative mutant, also prevents purinergic activation of AE. Therefore, tyrosine kinases play a
key role in acute regulation of intracellular pH and thus
in cell function including excitation-contraction coupling of the myocardium.
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