MOPRs in mouse islets of Langerhans modulate cell signaling and secretion

Le résumé fourni par la source

Most clinically and recreationally used opioids drugs act on the endogenous mu opioid receptor (MOPR). While MOPR is typically studied in the context of addiction and analgesia, decades of evidence indicates that they have a strong modulatory role on metabolism and glycemia. However, whether these effects are directly driven by MOPR actions on pancreatic islets remains poorly understood. Here we sought to comprehensively profile MOPRs on islets to assess how their activity shapes cellular physiology and secretion. First, we used RNA-seq, fluorescent in situ hybridization, and immunoblotting approaches to map islet expression. We observed robust expression of MOPR across multiple cell types in islets. Next, using a FRET-based approach, we show that MOPRs recruit canonical inhibitory pathways, reducing cAMP accumulation. Correspondingly, islets from constitutive MOPR knockout mice showed increased calcium influx and oscillations. However, MOPR knockout had no effect on insulin secretion, instead increase glucagon secretion. Surprisingly, while MOPR antagonism increased overall calcium, it reduced calcium oscillations and suppressed insulin secretion. By contrast MOPR agonism suppressed calcium, increased oscillations, and had no effect on overall hormone secretion. Collectively, these results suggest that MOPR can profoundly shape islet activity, with these effects likely driven by their actions on distinct cell types.

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