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1 Departments of Pediatrics, and 2 Physiology and Biophysics, Georgetown University Medical Center, Washington, District of Columbia 20007; 3 Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75235; 4 Department of Physiology, Case Western Reserve School of Medicine, Cleveland, Ohio 44106; 5 Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and 6 Department of Physiology, McGill University School of Medicine, Montreal, Canada H3G 1Y6
NHE3 activity is regulated by
phosphorylation/dephosphorylation processes and membrane recycling in
intact cells. However, the Na+/H+ exchanger
(NHE) can also be regulated by G proteins independent of cytoplasmic
second messengers, but the G protein subunits involved in this
regulation are not known. Therefore, we studied G protein subunit
regulation of NHE3 activity in renal brush-border membrane vesicles
(BBMV) in a system devoid of cytoplasmic components and second
messengers. Basal NHE3 activity was not regulated by Gs
or Gi, because antibodies to these G proteins by
themselves were without effect. The inhibitory effect of
D1-like agonists on NHE3 activity was mediated, in part, by
Gs, because it was partially reversed by
anti-Gs antibodies. Moreover, the amount of
Gs that coimmunoprecipitated with NHE3 was increased by
fenoldopam in both brush-border membranes and renal proximal tubule
cells. Furthermore, guanosine 5'-O-(3-thiotriphosphate)
but not guanosine 5'-O-(2-thiodiphosphate), the inactive analog
of GDP, increased the amount of Gs that
coimmunoprecipitated with NHE3. The 2-adrenergic
agonist, UK-14304 or pertussis toxin (PTX) alone had no effect on NHE3
activity, but UK-14304 and PTX treatment attenuated the
D1-like receptor-mediated NHE3 inhibition. The ability of
UK-14304 to attenuate the D1-like agonist effect was not
due to Gi, because the attenuation was not blocked by anti-Gi antibodies or by PTX.
Anti-G
common antibodies, by themselves, slightly inhibited NHE3 activity but had little effect on
D1-like receptor-mediated NHE3 inhibition. However,
anti-Gcommon antibodies reversed the effects of UK-14304
and PTX on D1-like agonist-mediated NHE3 inhibition. These
studies provide concrete evidence of a direct regulatory role for
Gs, independent of second messengers, in the
D1-like-mediated inhibition of NHE3 activity in rat renal BBMV. In addition, /
dimers of heterotrimeric G proteins appear to have a stimulatory effect on NHE3 activity in BBMV.
sodium/hydrogen exchanger isoforms; proximal tubule; kidney
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