Munc18-1 and Munc18-2 proteins modulate ß-cell Ca2+ sensitivity and kinetics of insulin exocytosis differently
Mandic, SA ...
Fast neurotransmission and slower hormone release share the same core fusion machinery consisting of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. In evoked ...neurotransmission, interactions between SNAREs and the Munc18-1 protein, a member of the Sec1/Munc18 (SM) protein family, are essential for exocytosis, whereas other SM proteins are dispensable. To address if the exclusivity of Munc18-1 demonstrated in neuroexocytosis also applied to fast insulin secretion, we characterized the presence and function of Munc18-1 and its closest homologue Munc18-2 in ß-cell stimulus-secretion coupling. We show that pancreatic ß-cells express both Munc18-1 and Munc18-2. The two Munc18 homologues exhibit different subcellular localization, and only Munc18-1 redistributes in response to glucose stimulation. However, both Munc18-1 and Munc18-2 augment glucose-stimulated hormone release. Ramp-like photorelease of caged Ca2+ and high resolution whole-cell patch clamp recordings show that Munc18-1 and Munc18-2 overexpression shift the Ca2+ sensitivity of the fastest phase of insulin exocytosis differently. In addition, we reveal that Ca2+ sensitivity of exocytosis in ß-cells depends on the phosphorylation status of the Munc18 proteins. Even though Munc18-1 emerges as the key SM-protein determining the Ca2+ threshold for triggering secretory activity in a stimulated ß-cell, Munc18-2 has the ability to increase Ca2+ sensitivity and thus mediates the release of fusion-competent granules requiring a lower cytoplasmic-free Ca2+ concentration, [Ca2+]i. Hence, Munc18-1 and Munc18-2 display distinct subcellular compartmentalization and can coordinate the insulin exocytotic process differently as a consequence of the actual [Ca2+]i.
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