NDLI: Functional Differences in Ionic Regulation between Alternatively Spliced Isoforms of the Na+-Ca2+ Exchanger from Drosophila melanogaster

Content Provider	PubMed Central
Author	Omelchenko, Alexander Dyck, Christopher Mark, Hnatowich Buchko, John Nicoll, Debora A. Philipson, Kenneth D. Hryshko, Larry V.
Copyright Year	1998
Abstract	Ion transport and regulation were studied in two, alternatively spliced isoforms of the Na+-Ca2+ exchanger from Drosophila melanogaster. These exchangers, designated CALX1.1 and CALX1.2, differ by five amino acids in a region where alternative splicing also occurs in the mammalian Na+-Ca2+ exchanger, NCX1. The CALX isoforms were expressed in Xenopus laevis oocytes and characterized electrophysiologically using the giant, excised patch clamp technique. Outward Na+-Ca2+ exchange currents, where pipette Ca2+ o exchanges for bath Na+ i, were examined in all cases. Although the isoforms exhibited similar transport properties with respect to their Na+ i affinities and current–voltage relationships, significant differences were observed in their Na+ i- and Ca2+ i-dependent regulatory properties. Both isoforms underwent Na+ i-dependent inactivation, apparent as a time-dependent decrease in outward exchange current upon Na+ i application. We observed a two- to threefold difference in recovery rates from this inactive state and the extent of Na+ i-dependent inactivation was approximately twofold greater for CALX1.2 as compared with CALX1.1. Both isoforms showed regulation of Na+-Ca2+ exchange activity by Ca2+ i, but their responses to regulatory Ca2+ i differed markedly. For both isoforms, the application of cytoplasmic Ca2+ i led to a decrease in outward exchange currents. This negative regulation by Ca2+ i is unique to Na+-Ca2+ exchangers from Drosophila, and contrasts to the positive regulation produced by cytoplasmic Ca2+ for all other characterized Na+-Ca2+ exchangers. For CALX1.1, Ca2+ i inhibited peak and steady state currents almost equally, with the extent of inhibition being ≈80%. In comparison, the effects of regulatory Ca2+ i occurred with much higher affinity for CALX1.2, but the extent of these effects was greatly reduced (≈20–40% inhibition). For both exchangers, the effects of regulatory Ca2+ i occurred by a direct mechanism and indirectly through effects on Na+ i-induced inactivation. Our results show that regulatory Ca2+ i decreases Na+ i-induced inactivation of CALX1.2, whereas it stabilizes the Na+ i-induced inactive state of CALX1.1. These effects of Ca2+ i produce striking differences in regulation between CALX isoforms. Our findings indicate that alternative splicing may play a significant role in tailoring the regulatory profile of CALX isoforms and, possibly, other Na+-Ca2+ exchange proteins.
Starting Page	691
File Format	PDF
ISSN	15407748
e-ISSN	15407748
Journal	The Journal of General Physiology
Issue Number	5
Volume Number	111
Language	English
Publisher	The Rockefeller University Press
Publisher Date	1998-05-01
Access Restriction	Open
Rights Holder	The Rockefeller University Press
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Physiology

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Functional Differences in Ionic Regulation between Alternatively Spliced Isoforms of the Na+-Ca2+ Exchanger from Drosophila melanogaster

Functional Differences in Ionic Regulation between Alternatively Spliced Isoforms of the Na+-Ca2+ Exchanger from Drosophila melanogaster

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