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Review
, 45 (8), e37

Signaling Mechanisms of Glucose-Induced F-actin Remodeling in Pancreatic Islet β Cells

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Review

Signaling Mechanisms of Glucose-Induced F-actin Remodeling in Pancreatic Islet β Cells

Michael A Kalwat et al. Exp Mol Med.

Abstract

The maintenance of whole-body glucose homeostasis is critical for survival, and is controlled by the coordination of multiple organs and endocrine systems. Pancreatic islet β cells secrete insulin in response to nutrient stimuli, and insulin then travels through the circulation promoting glucose uptake into insulin-responsive tissues such as liver, skeletal muscle and adipose. Many of the genes identified in human genome-wide association studies of diabetic individuals are directly associated with β cell survival and function, giving credence to the idea that β-cell dysfunction is central to the development of type 2 diabetes. As such, investigations into the mechanisms by which β cells sense glucose and secrete insulin in a regulated manner are a major focus of current diabetes research. In particular, recent discoveries of the detailed role and requirements for reorganization/remodeling of filamentous actin (F-actin) in the regulation of insulin release from the β cell have appeared at the forefront of islet function research, having lapsed in prior years due to technical limitations. Recent advances in live-cell imaging and specialized reagents have revealed localized F-actin remodeling to be a requisite for the normal biphasic pattern of nutrient-stimulated insulin secretion. This review will provide an historical look at the emergent focus on the role of the actin cytoskeleton and its regulation of insulin secretion, leading up to the cutting-edge research in progress in the field today.

Figures

Figure 1
Figure 1
Biphasic glucose-stimulated insulin secretion from perfused mouse islets. In response to a square-wave increase in glucose concentration, islet β cells dock/fuse ∼50–100 granules in the first phase of secretion. First phase is temporally defined, complete within ∼10 min of glucose stimulation, thought to be accounted for in large part by the readily releasable pool of granules. First phase is immediately followed by a second phase, with second phase being lower in amplitude but persistent in the presence of glucose stimulation over hours of time, and thus not temporally limited. Second phase is presumed to require storage/reserve pools of granules that can be recruited to the plasma membrane for secretion.
Figure 2
Figure 2
Cortical filamentous actin (F-actin) remodeling in β cells regulates insulin granule exocytosis. (a) Schematic of a pancreatic β cell depicts how readily releasable pool (RRP) granules are docked at the membrane and reserve pool granules are in a more intracellular storage pool. Cortical F-actin can regulate access of reserve pool granules to the readily releasable pool. (b) Microscopic analysis of β cell-actin remodeling is often performed on cells attached to coverslips (a very different environment from the three-dimensional islet architecture) where it is important to note that focal adhesions/stress fibers form at the cell attachment interface. Conversely, cortical F-actin is visualized at the cell perimeter when focused at the mid plane of the cell. This distinction is particularly important in differentiating cortical F-actin remodeling from other types of actin remodeling.
Figure 3
Figure 3
Pathways impinging specifically on glucose-mediated F-actin remodeling in the β cell. The β cell responds to certain insulin secretagogues by remodeling its cortical filamentous actin (F-actin). Glucose metabolism can signal to Cdc42, at least partially though β-Pix, to activate p21-activated kinase (PAK1) and evoke Rac1 activation. Under basal conditions, Cdc42 and Rac1 are held inactive by guanine nucleotide dissociation inhibitor (GDI) proteins Caveolin-1 and RhoGDI. In addition, GLP-1 activation of GLP-1R can lead to increased cAMP and PKA activation which can activate SAD-A kinase and feed into the PAK1 pathway. Active PAK1 signals to multiple effectors, such as Rac1, to facilitate F-actin remodeling. PAK1 is important for Raf/MEK activation, leading to ERK activation. PAK1 (and possibly ERK as well) may then signal to myosin light-chain kinase (MLCK)-myosin IIA (MyoIIA) to further mediate F-actin remodeling. Focal adhesion kinase (FAK) participates in cross-talk with ERK, which may indirectly modulate cortical F-actin remodeling. The F-actin binding and severing protein Gelsolin complexes directly with the t-SNARE (soluble N-ethylmaleimide sensitive factor attachment receptor) protein Syntaxin 4, ultimately impacting SNARE-mediated insulin exocytosis. Syntaxin 4 in particular is essential for second-phase insulin release, complexing with the other t-SNARE protein synaptosomal-associated protein of 25 kDa (SNAP-25) (or SNAP-23) and the incoming granule vesicle-SNARE, VAMP2.

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