EXPRESSION AND FUNCTION OF CALCINEURIN IN THE MAMMALIAN NEPHRON - PHYSIOLOGICAL ROLES, RECEPTOR SIGNALING, AND ION-TRANSPORT

Protein phosphorylation is central to the regulation of sodium transpo rt and other cellular processes in the nephron, Complex interactions b etween protein kinases and phosphatases catalyze the reversible phosph orylation of ion transporting proteins on the apical and basolateral s urfaces of renal epithelia. Although the role of protein kinases in re gulating sodium transport has been extensively studied, the function o f phosphatases in the nephron is less well understood. Calcineurin is a serine-threonine phosphatase that was shown to be the target of cycl osporin A (CsA) and FK-506 in lymphocytes. Calcineurin exists in the c ytosol as a heterotrimeric protein composed of an alpha-catalytic subu nit, beta-regulatory subunit, and calmodulin; its activity depends on calcium and calmodulin. Three isoforms of the alpha-subunit (alpha-1, alpha-2, alpha-3) and two isoforms of the beta-subunit (beta-1 and bet a-2) of calcineurin have been identified. In proximal tubules, alpha-1 isoforms are predominant and exceed alpha-2 expression by fourfold. I n the CCD, alpha-1 and alpha-2 expression are approximately equal, whe reas alpha-2 subunit expression is greatest in medullary thick ascendi ng limbs (mTAL), alpha-3 was not detected in any nephron segment, Calc ineurin phosphatase activity in the proximal tubule is approximately 1 0-fold higher than in the connecting tubules (CNT), cortical collectin g ducts (CCD), or the mTAL. Protein phosphatases 1 and 2a are also exp ressed in CCD, and only protein phosphatase 1 can be detected in the p roximal tubule, Calcineurin influences basal and stimulated Na/K-ATPas e activity in the proximal and distal nephron, In the CCD, CsA or FK-5 06 decrease Na/K-ATPase activity by 35% and 85%, respectively; Na/K-AT Pase activity in mTAL is decreased by 53% and 56%. Activation of membr ane receptors, including adrenergic, dopamanergic, and angiotensin I r eceptors, also regulates Na/K-ATPAse activity through processes that i nvolve calcineurin. Lastly, steroid hormones including glucocorticoids and mineralocorticoids appear to activate calcineurin phosphatase act ivity, The mechanism is independent of transcription and appears to in volve mechanisms involving heat shock proteins associated with the ste roid receptor complex. (C) 1997 by the National Kidney Foundation, Inc .