Abstract
Ca2+/calmodulin-stimulated group I adenylyl cyclase (AC) isoforms AC1 and AC8 have been involved in nociceptive processing and morphine responses. However, whether AC3, another member of group I ACs, is involved in nociceptive transmission and regulates opioid receptor signaling remains elusive. Here, we report that conditional KO of AC3 (AC3 CKO) in L3 and L4 DRGs robustly facilitated the mouse nociceptive responses, decreased voltage-gated potassium (Kv) channel currents, and increased neuronal excitability. Furthermore, we report AC3 CKO eliminated the analgesic effect of κ-opioid receptor (KOR) agonist and its inhibition on Kv channel by classical Gαi/o signaling or nonclassical direct interaction of KOR and AC3 proteins. Interestingly, significantly upregulated AC1 level and cAMP concentration were detected in AC3-deficient DRGs. Inhibition of AC1 completely reversed cAMP upregulation, neuronal excitability enhancement, and nociceptive behavioral hypersensitivity in AC3-CKO mice. Our findings suggest a crucial role of peripheral AC3 in nociceptive modulation and KOR opioid analgesia.
Highlights
Mammalian adenylyl cyclase (AC) is an important enzyme family catalyzing the conversion of ATP into the second messenger cAMP in G protein coupled receptor (GPCR) signaling
Our previous study showed that AC3 immunoreactivity was mainly expressed in smalland medium-diameter CGRP-positive peptidergic sensory neurons in the Dorsal root ganglia (DRG) (25), which are thought to be important in nociceptive transmission (30)
We confirmed the distribution of AC3 mRNA in the DRG and compared its proportion in different DRG neurons by RNAscope in situ hybridization combined with immunofluorescence labeling
Summary
Mammalian adenylyl cyclase (AC) is an important enzyme family catalyzing the conversion of ATP into the second messenger cAMP in G protein coupled receptor (GPCR) signaling. Studies have demonstrated that AC isoforms are expressed ubiquitously in distinct region and subcellular location of the central nervous system (CNS) and contribute to various pathophysiological processes including learning, memory, anxiety, depression, chronic pain and drug abuse (2-7). Among these AC isoforms, AC1, AC3 and AC8 can be directly stimulated by Ca2+/calmodulin in vitro and are classified into the Group I AC isoforms (8-11). AC1 knockout and AC1/AC8 double knockout (DKO) mice exhibit robust reduced formalin and CFA inflammatory pain responses (14-18). Pharmacological inhibition of AC1 can effectively relieve inflammatory and neuropathic pain in both mice and rats (17, 19, 20). Whether AC3, another member of Group I ACs, is implicated in nociceptive processing remains unclear
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