The nuts and bolts of the platelet release reaction

Abstract

Secretion is essential to many of the roles that platelets play in the vasculature, e.g., thrombosis, angiogenesis, and inflammation, enabling platelets to modulate the microenvironment at sites of vascular lesions with a myriad of bioactive molecules stored in their granules. Past studies demonstrate that granule cargo release is mediated by Soluble NSF Attachment Protein Receptor (SNARE) proteins, which are required for granule-plasma membrane fusion. Several SNARE regulators, which control when, where, and how the SNAREs interact, have been identified in platelets. Additionally, platelet SNAREs are controlled by post-translational modifications, e.g., phosphorylation and acylation. Although there have been many recent insights into the mechanisms of platelet secretion, many questions remain: have we identified all the important regulators, does calcium directly control the process, and is platelet secretion polarized. In this review, we focus on the mechanics of platelet secretion and discuss how the secretory machinery functions in the pathway leading to membrane fusion and cargo release.

Keywords: Exocytosis; Munc13; Munc18; Rab; SNAREs; STXBP5.

Figure 1. Pathway of SNARE-Mediated Platelet Granule Release

Platelet exocytosis is a pathway of protein-protein interactions leading from 1) granule docking, 2) SNARE engagement to 3) membrane fusion and 4) cargo release. The interactions and their proposed order of occurrence are depicted in the schematic. The machinery which could be on the granules includes: v-SNAREs (Vesicle Associated Membrane Protein/VAMPs); Munc13-4 and synaptotagmin like protein (SLP); small GTPases Rab and Ral; and the Exocyst complex. The machinery on the plasma membrane includes: t-SNARE heterodimer of Syntaxin 11 and SNAP 23; the Syntaxin-chaperone Munc18b; and the t-SNARE regulator STXBP5/Tomosyn-1. Also depicted are domains in each protein which contribute to protein function and thus platelet exocytosis: blue lines, C2 domains in Munc13-4 and SLP; brown line, Munc homology domain in Munc13-4; red lines, SLP homology domain in SLP; rounded rectangles, SNARE domain.