Regulation of Calcium Oscillations in β-Cells by Co-activated Cannabinoid Receptors

Pharmacological treatment of pancreatic β cells targeting cannabinoid receptors 1 and 2 (CB1 and CB2) has been shown to result in significant effects on insulin release, possibly by modulating intracellular calcium levels ([Ca²⁺]_i). It is unclear how the interplay of CB1 and CB2 affects insulin secretion. Here, we demonstrate by the use of highly specific receptor antagonists and the recently developed photo-releasable endocannabinoid 2-arachidonoylglycerol that both receptors have counteracting effects on cytosolic calcium oscillations. We further show that both receptors are juxtaposed in a way that increases [Ca²⁺]_i oscillations in silent β cells but dampens them in active ones. This study highlights a functional role of CB1 and CB2 acting in concert as a compensator/attenuator switch for regulating β cell excitability.