title: The adenylyl cyclase inhibitor MDL-12,330A potentiates insulin secretion via blockade of voltage-dependent K(+) channels in pancreatic beta cells.
abstract: OBJECTIVE
  Adenylyl cyclases (ACs) play important role in regulating pancreatic beta cell growth, survival and secretion through the synthesis of cyclic AMP (cAMP). MDL-12,330A and SQ 22536 are two AC inhibitors used widely to establish the role of ACs. The goal of this study was to examine the effects of MDL-12,330A and SQ 22536 on insulin secretion and underlying mechanisms.
  
  
  METHODS
  Patch-clamp recording, Ca(2+) fluorescence imaging and radioimmunoassay were used to measure outward K(+) currents, action potentials (APs), intracellular Ca(2+) ([Ca(2+)]i) and insulin secretion from rat pancreatic beta cells.
  
  
  RESULTS
  MDL-12,330A (10 µmol/l) potentiated insulin secretion to 1.7 times of control in the presence of 8.3 mmol/l glucose, while SQ 22536 did not show significant effect on insulin secretion. MDL-12,330A prolonged AP durations (APDs) by inhibiting voltage-dependent K(+) (KV) channels, leading to an increase in [Ca(2+)]i levels. It appeared that these effects induced by MDL-12,330A did not result from AC inhibition, since SQ 22536 did not show such effects. Furthermore, inhibition of the downstream effectors of AC/cAMP signaling by PKA inhibitor H89 and Epac inhibitor ESI-09, did not affect KV channels and insulin secretion.
  
  
  CONCLUSIONS
  The putative AC inhibitor MDL-12,330A enhances [Ca(2+)]i and insulin secretion via inhibition of KV channels rather than AC antagonism in beta cells, suggesting that the non-specific effects is needed to be considered for the right interpretation of the experimental results using this agent in the analyses of the role of AC in cell function.
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Guo
authors.forename: Jingying
authors.initials: J
authors.lastname: Gao
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Wan
authors.initials: W
authors.lastname: Zhang
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Liang
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wu
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Liu
authors.forename: Jianping
authors.initials: J
authors.lastname: Weng
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004594:Electrophysiology; D005947:Glucose / Q000378:metabolism; D007097:Imines / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D007097:Imines; D007328:Insulin; D024642:Potassium Channels, Voltage-Gated; C014925:RMI 12330A; D000242:Cyclic AMP; D005947:Glucose; D002118:Calcium