Effects of Cannabinoids on Ion Channels of Pancreatic Beta Cells

Abstract

The function of the beta cell of the pancreatic islet is to sense minute changes in blood glucose levels and secrete insulin to maintain euglycemia. Though this secretion is governed chiefly by glucose, other chemical factors such as insulin itself and the incretin hormones also modulate this function. Peliminary evidence in our lab indicates that endocannabinoids are important negative regulators of insulin secretion. Beta cells are electrically excitable and undergo depolarization upon glucose stimulated insulin secretion resulting from closure of the K(ATP) channels. As a consequence, the calcium channels open, intracellular levels of calcium rise and exocytosis of the insulin secretory granules occurs. In addition to the K(ATP) channels and the calcium channels, beta cells also possess an array of ion channels that generate the complex electrical waveforms and participate to varying degrees in the regulation of the membrane potential.Using rodent beta cells we investigated the effects of cannabinoids on some of these ion channels. Thus, 10 μM 2-arachidonylglycerol (2-AG) decreased the amplitude of the delayed rectifier current by about 40%. Simple washing did not reverse this blockade, and the addition of the cannabinoid receptor 1 (CB1) antagonist AM 251 (1 μ) also had no effect. However, the blockade was completely reversed by washing with lipid free bovine serum albumin. Moreover, the CB1 agonist, WIN-55,212-2(1 μM ), an indole derivative structurally unrelated to the lipid 2-AG, had no antagonistic effect on the delayed rectifier. Taken together, these results suggest that the block was independent of the CB1 receptor and was mediated instead via the plasma membrane. Cannabinoid blockade of both sodium and HVA calcium currents were similar to the effects on the delayed rectifier.