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 transport and other cellular processes in the nephron. Complex interactions between protein kinases and phosphatases catalyze the reversible phosphorylation of ion transporting proteins on the apical and basolateral surfaces of renal epithelia. Although the role of protein kinases in regulating sodium transport has been extensively studied, the function of phosphatases in the nephron is less well understood. Calcineurin is a serine-threonine phosphatase that was shown to be the target of cyclosporin A (CsA) and FK-506 in lymphocytes. Calcineurin exists in the cytosol as a heterotrimeric protein composed of an alpha-catalytic subunit, 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 beta-2) of calcineurin have been identified. In proximal tubules, alpha-1 isoforms are predominant and exceed alpha-2 expression by fourfold. In the CCD, alpha-1 and alpha-2 expression are approximately equal, whereas alpha-2 subunit expression is greatest in medullary thick ascending limbs (mTAL). Alpha-3 was not detected in any nephron segment. Calcineurin phosphatase activity in the proximal tubule is approximately 10-fold higher than in the connecting tubules (CNT), cortical collecting ducts (CCD), or the mTAL. Protein phosphatases 1 and 2a are also expressed in CCD, and only protein phosphatase 1 can be detected in the proximal tubule. Calcineurin influences basal and stimulated Na/ K-ATPase activity in the proximal and distal nephron. In the CCD, CsA or FK-506 decrease Na/K-ATPase activity by 35% and 85%, respectively; Na/K-ATPase activity in mTAL is decreased by 53% and 56%. Activation of membrane receptors, including adrenergic, dopamanergic, and angiotensin I receptors, also regulates Na/K-ATPAse activity through processes that involve calcineurin. Lastly, steroid hormones including glucocorticoids and mineralocorticoids appear to activate calcineurin phosphatase activity. The mechanism is independent of transcription and appears to involve mechanisms involving heat shock proteins associated with the steroid receptor complex.
Tumlin
J A
JA
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. jtumlin@emory.edu
D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000502:physiology; D002147:Calmodulin / Q000502:physiology; D004848:Epithelium / Q000201:enzymology; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D017136:Ion Transport; D007527:Isoenzymes / Q000737:chemistry / Q000502:physiology; D007679:Kidney Medulla / Q000201:enzymology; D007684:Kidney Tubules / Q000201:enzymology; D007687:Kidney Tubules, Proximal / Q000201:enzymology; D008322:Mammals; D009399:Nephrons / Q000201:enzymology*; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology; D054645:Protein Phosphatase 1; D017983:Receptors, Catecholamine / Q000502:physiology; D011987:Receptors, Steroid / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
D000305:Adrenal Cortex Hormones; D002147:Calmodulin; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D017983:Receptors, Catecholamine; D011987:Receptors, Steroid; D012964:Sodium; D011494:Protein Kinases; D019703:Calcineurin; D054645:Protein Phosphatase 1; D010744:Phosphoric Monoester Hydrolases; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium