Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Little is known about collecting duct adenylyl cyclase (AC) isoforms or regulation in the mouse. We performed RT-PCR for AC isoforms 1-9 in microdissected cortical (CCD) and outer medullary (OMCD) and acutely isolated inner medullary (IMCD) collecting duct. All collecting duct regions contained AC3, AC4, and AC6 mRNA, while CCD and OMCD, but not IMCD, also contained AC5 mRNA. Acutely isolated IMCD expressed AC3, AC4, and AC6 proteins by Western blot analysis. The mIMCD3 cell line expressed AC2, AC3, AC4, AC5, and AC6 mRNA; M-1 CCD cells expressed AC2, 3, 4, and 6, while mpkCCD cell lines contained AC3, AC4, and AC6 mRNA. AVP stimulated cAMP accumulation in acutely isolated mouse IMCD; this was reduced by chelation of extracellular calcium (EGTA) and almost completely abolished by blockade of calmodulin (W-7). Blockade of calmodulin kinase with KN-93 or endoplasmic reticulum calcium ATPase (thapsigargin) also reduced the AVP response. A similar inhibitory effect of W-7, KN-93, and thapsigargin was seen on forskolin-stimulated cAMP content in acutely isolated mouse IMCD. These three agents had the same pattern of blockade of AVP- or forskolin-stimulated AC activity in acutely isolated rat IMCD. AVP responsiveness in primary cultures of mouse IMCD was also reduced by W-7, KN-93, and thapsigargin. Small interfering RNA (siRNA) designed to knock down AC3 or AC6 in primary cultured mouse IMCD significantly reduced AVP-stimulated cAMP accumulation. Together, these data are consistent with a role of AC3 and AC6 in the activation of mouse collecting duct by AVP.
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PMID:Characterization of vasopressin-responsive collecting duct adenylyl cyclases in the mouse. 2003 13

cAMP is a key mediator of connecting tubule and collecting duct (CD) Na(+) and water reabsorption. Studies performed in vitro have suggested that CD adenylyl cyclase (AC)3 partly mediates the actions of vasopressin; however, the physiological role of CD AC3 has not been determined. To assess this, mice were developed with CD-specific disruption of AC3 [CD AC3 knockout (KO)]. Inner medullary CDs from these mice exhibited 100% target gene recombination and had reduced ANG II- but not vasopressin-induced cAMP accumulation. However, there were no differences in urine volume, urinary urea excretion, or urine osmolality between KO and control mice during normal water intake or varying degrees of water restriction in the presence or absence of chronic vasopressin administration. There were no differences between CD AC3 KO and control mice in arterial pressure or urinary Na(+) or K(+) excretion during a normal or high-salt diet, whereas plasma renin and vasopressin concentrations were similar between the two genotypes. Patch-clamp analysis of split-open cortical CDs revealed no difference in epithelial Na(+) channel activity in the presence or absence of vasopressin. Compensatory changes in AC6 were not responsible for the lack of a renal phenotype in CD AC3 KO mice since combined CD AC3/AC6 KO mice had similar arterial pressure and renal Na(+) and water handling compared with CD AC6 KO mice. In summary, these data do not support a significant role for CD AC3 in the regulation of renal Na(+) and water excretion in general or vasopressin regulation of CD function in particular.
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PMID:Lack of an effect of collecting duct-specific deletion of adenylyl cyclase 3 on renal Na+ and water excretion or arterial pressure. 2443 Dec 4

Abstract Adenylyl cyclase (AC)-stimulated cAMP is a key mediator of collecting duct (CD) Na and water transport. AC isoforms 3, 4, and 6 are expressed in the CD. Our group demonstrated that AC6, but not AC3, is involved in regulating CD Na and water transport. However, the role of AC4 in such regulation remains unknown. Therefore, we generated mice with loxP-flanked critical exons in the Adcy4 gene and bred with mice expressing the aquaporin-2/Cre recombinase transgene to yield CD principal cell-specific knockout of AC4 (CD AC4 KO). Isolated inner medullary CD showed 100% genomic target gene recombination in CD AC4 KO mice, while microdissected cortical CD and renal papillary AC4 mRNA was significantly reduced in CD AC4 KO mice. CD AC4 KO had no effect on vasopressin (AVP)-stimulated cAMP generation in the inner medulla. Water intake, urine volume, and urine osmolality were similar between CD AC4 KO and control mice during normal or restricted water intake. Sodium intake, urinary Na excretion, and blood pressure on a normal-, high-, or low-Na diet were not affected by CD AC4 KO. Moreover, there were no differences in plasma AVP or plasma renin concentration between CD AC4 KO and control mice. In summary, these data suggest that CD AC4 does not play a role in the physiologic regulation of CD Na and water handling.
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PMID:Adenylyl cyclase 4 does not regulate collecting duct water and sodium handling. 2476 May 29