Inhibition of adenylyl cyclase 1 (AC1) and exchange protein directly activated by cAMP (EPAC) restores ATP-sensitive potassium (K_ATP) channel activity after chronic opioid exposure.

ABSTRACT: Prolonged exposure to Gαi/o receptor agonists such as opioids can lead to a sensitization of adenylyl cyclases (ACs), resulting in heterologous sensitization or cyclic AMP (cAMP) overshoot. The molecular consequences of cAMP overshoot are not well understood, but this adaptive response is suggested to play a critical role in the development of opioid tolerance and withdrawal. We found that genetic reduction of AC1 and simultaneous upregulation of ATP-sensitive potassium (K_ATP) channel subunits, SUR1 or Kir6.2, significantly attenuated morphine tolerance and reduced naloxone-precipitated withdrawal. In vitro models utilized an EPAC2-GFP-cAMP biosensor to investigate sensitization of adenylyl cyclase in SH-SY5Y neuroblastoma cells and HEKΔAC3/6 knockout cells. Acute applica

SUBMITTER: Klein AH 

PROVIDER: S-EPMC11838493 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature