Recent new insights into the role of SNARE and associated proteins in insulin granule exocytosis

Abstract

Initial work on the exocytotic machinery of predocked insulin secretory granules (SGs) in pancreatic β-cells mimicked the SNARE hypothesis work in neurons, which includes SM/SNARE complex and associated priming proteins, fusion clamps and Ca 2+ sensors. However, β-cell SGs, unlike neuronal synaptic vesicles, exhibit a biphasic secretory response that requires additional distinct features in exocytosis including newcomer SGs that undergo minimal docking time at the plasma membrane (PM) before fusion and multi-SG (compound) fusion. These exocytotic events are mediated by Munc18/SNARE complexes distinct from that which mediates predocked SG fusion. We review some recent insights in SNARE complex assembly and the promiscuity in SM/SNARE complex formation, whereby both contribute to conferring different insulin SG fusion kinetics. Some SNARE and associated proteins play non-fusion roles, including tethering SGs to Ca 2+ channels, SG recruitment from cell interior to PM, and inhibitory SNAREs that block the action of profusion SNAREs. We discuss new insights into how sub-PM cytoskeletal mesh gates SG access to the PM and the targeting of SG exocytosis to PM domains in functionally polarized β-cells within intact islets. These recent developments have major implications on devising clever SNARE replacement therapies that could restore the deficient insulin secretion in diabetic islet β-cells. We discuss each of these exciting developments.

Removing the Gβγ-SNAP25 brake on exocytosis enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity

“…We took advantage of the βγ-SNAP25 interaction and its ability to serve as a brake on secretion to determine if limiting this physiologic inhibitory pathway could affect insulin secretion and/or weight gain in response to a high fat diet. Though SNAP25 is a well-known component of the insulin exocytosis machinery (13)(14)(15), we observed no alteration in GSIS from SNAP25 Δ3/Δ3 mice. However, adiposity and glucose homeostasis were markedly improved.…”

“…SNAP25 Δ3/Δ3 mice have marked improvement in glucose homeostasis. Our initial hypothesis was that this would be present because an improvement in insulin secretion as SNAP25 has been show to transduce signals that inhibit insulin secretion (13)(14)(15). In fact, we found that SNAP25 Δ3/Δ3 mice have normal β-cell function and the improvement in glucose homeostasis is because of an improvement in insulin action.…”

“…The SNAP25 Δ3/Δ3 mouse has demonstrated the importance of the Gβγ-SNARE pathway in a number of neurological processes, including stress and pain processing, as well as long-term potentiation (6) and spatial memory (5). We hypothesized that the SNAP25 Δ3/Δ3 mouse may have an altered metabolic phenotype because neurological processes use SNAREdependent signals to regulate a number of metabolically important processes, such as feeding behavior, energy balance, and thermoregulation (7-12), and the secretion of important metabolic hormones, such as insulin (13)(14)(15).…”

“…The SNAP25 Δ3/Δ3 mouse has demonstrated the importance of the Gβγ-SNARE pathway in a number of neurological processes, including stress and pain processing, as well as long-term potentiation (6) and spatial memory (5). We hypothesized that the SNAP25 Δ3/Δ3 mouse may have an altered metabolic phenotype because neurological processes use SNAREdependent signals to regulate a number of metabolically important processes, such as feeding behavior, energy balance, and thermoregulation (7-12), and the secretion of important metabolic hormones, such as insulin (13)(14)(15).Metabolic diseases, such as diabetes and obesity, are estimated to have an annual global economic impact in the trillions of (US) dollars (16)(17)(18)(19)(20). The therapeutic value of the recently developed glutides and gliptins highlights the benefits of pharmacological agents that augment glucose stimulated insulin secretion (GSIS) (21).We hypothesized that the SNAP25Δ3 mutation would similarly enhance GSIS because previous studies have indicated that norepinephrine inhibits insulin exocytosis via the α2A adrenergic receptor (AR) through Gβγ inhibition of SNARE in the pancreatic β-cell (22).…”

Microtubules regulate pancreatic beta cell heterogeneity via spatiotemporal control of insulin secretion hot spots

“…underlying this timing are believed to be associated with the availability of secretion-ready 65 insulin vesicles that do not depend on changes in Ca 2+ levels (Gaisano, 2017). m 66…”