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The Cytoplasmic Domain of the Na+/H+ Exchangers (NHEs) Dictates the Nature of the Hormonal Response: Behavior of a Chimeric Human NHE1/Trout βNHE Antiporter
Franck Borgese, Murielle Malapert, Bruno Fievet, Jacques Pouyssegur and Rene Motais
Proceedings of the National Academy of Sciences of the United States of America
Vol. 91, No. 12 (Jun. 7, 1994), pp. 5431-5435
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/2364753
Page Count: 5
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Studies of the effect of cAMP on the cloned Na+/H+ exchangers (NHEs) are difficult to interpret as variable results have been reported for the different isoforms when expressed in various cell types. We took advantage of the fact that the human NHE1 and the trout erythrocyte βNHE, when expressed in the same cell line, PS120, respond differently to cAMP (NHE1 is insensitive, βNHE is activated) to analyze the molecular mechanisms of cAMP activation. We constructed both a chimera between NHE1 and βNHE and a set of βNHE mutants to delineate the critical parts of the molecule involved in the activation process. NHE1 becomes cAMP stimulated when its cytoplasmic domain is replaced by the cytoplasmic domain of βNHE; thus, the cytoplasmic C terminus of βNHE, which contains two cAMP-dependent consensus sequences, is essential to confer cAMP dependence. Serine to glycine substitution of only one of the two protein kinase A (PKA) consensus sites decreased by 60% the ability of cAMP to activate Na+/H+ exchange. Simultaneous Ser to Gly substitution of the two PKA consensus sites decreased the cAMP-mediated activation by 72%. The residual activation required a cytoplasmic fragment (aa 559-661) that contains four sequences considered likely as putative PKA consensus sites. The results obtained with the chimeric NHE also demonstrated that if the cytoplasmic C terminus is crucially involved in the hormonal activation, the rate of Na+/H+ exchange so induced can be modulated by the nature of the interaction between the N- and C-terminal domains.
Proceedings of the National Academy of Sciences of the United States of America © 1994 National Academy of Sciences