Calmodulin-sensitive adenylyl cyclases mediate AVP-dependent cAMP production and Cl- secretion by human autosomal dominant polycystic kidney cells.

Abstract

In autosomal dominant polycystic kidney disease (ADPKD), binding of AVP to the V2 receptor (V2R) increases cAMP and accelerates cyst growth by stimulating cell proliferation and Cl(-)-dependent fluid secretion. Basal cAMP is elevated in human ADPKD cells compared with normal human kidney (NHK) cells. V2R mRNA levels are elevated in ADPKD cells; however, AVP caused a greater increase in global cAMP in NHK cells, suggesting an intrinsic difference in cAMP regulation. Expression, regulatory properties, and receptor coupling of specific adenylyl cyclases (ACs) provide temporal and spatial regulation of the cAMP signal. ADPKD and NHK cells express mRNAs for all nine ACs. Ca(2+)-inhibited ACs 5 and 6 are increased in ADPKD cells, while Ca(2+)/CaM-stimulated ACs 1 and 3 are downregulated. ACs 1, 3, 5, and 6 were detected in cyst cells in situ, and codistribution with aquaporin-2 suggests that these cysts were derived from collecting ducts. To determine the contribution of CaM-sensitive ACs to AVP signaling, cells were treated with W-7, a CaM inhibitor. W-7 decreased AVP-induced cAMP production and Cl(-) secretion by ADPKD cells. CaMKII inhibition increased AVP-induced cAMP, suggesting that cAMP synthesis is mediated by AC3. In contrast, CaM and CaMKII inhibition in NHK cells did not affect AVP-induced cAMP production. Restriction of intracellular Ca(2+) switched the response in NHK cells, such that CaM inhibition decreased AVP-induced cAMP production. We suggest that a compensatory response to decreased Ca(2+) in ADPKD cells switches V2R coupling from Ca(2+)-inhibited ACs 5/6 to Ca(2+)/CaM-stimulated AC3, to mitigate high cAMP levels in response to continuous AVP stimulation.

• Authors: Cibele S Pinto, Gail A Reif, Emily Nivens, Corey White, Darren P Wallace
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 303 Issue 10 Pg. F1412-24 (Nov 15 2012) ISSN: 1522-1466 [Electronic] United States
• PMID: 22952279 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aquaporin 2
• Calmodulin
• Chlorides
• Receptors, Vasopressin
• Sulfonamides
• Arginine Vasopressin
• W 7
• Cyclic AMP
• Adenylyl Cyclases

Topics

• Adenylyl Cyclases (metabolism)
• Aquaporin 2 (metabolism)
• Arginine Vasopressin (metabolism)
• Calmodulin (antagonists & inhibitors, metabolism)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Chlorides (metabolism)
• Cyclic AMP (biosynthesis)
• Down-Regulation
• Epithelial Cells (drug effects, metabolism)
• Humans
• Kidney (drug effects, metabolism)
• Polycystic Kidney, Autosomal Dominant (metabolism)
• Receptors, Vasopressin (metabolism)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)