Secrets of platelet exocytosis - what do we really know about platelet secretion mechanisms?

Abstract

Upon activation by extracellular matrix components or soluble agonists, platelets release in excess of 300 active molecules from intracellular granules. Those factors can both activate further platelets and mediate a range of responses in other cells. The complex microenvironment of a growing thrombus, as well as platelets' roles in both physiological and pathological processes, require platelet secretion to be highly spatially and temporally regulated to ensure appropriate responses to a range of stimuli. However, how this regulation is achieved remains incompletely understood. In this review we outline the importance of regulated secretion in thrombosis as well as in 'novel' scenarios beyond haemostasis and give a detailed summary of what is known about the molecular mechanisms of platelet exocytosis. We also discuss a number of theories of how different cargoes could be released in a tightly orchestrated manner, allowing complex interactions between platelets and their environment.

Keywords: SNAREs; familial haemophagocytic lymphohistiocytosis; mouse models; platelet secretion; platelet signalling.

Fig 1

An illustration of platelet granule contents and their important physiological (green) and pathological (red) correlates. Alpha granules contain cargoes with often opposing actions (e.g., angiogenesis and coagulation-related factors), hence a mechanism(s) ensuring tight spatial and temporal regulation of secretion is likely to be in place to allow platelets to exert their many functions. It should be noted that although functions are assigned to each cargo, many cargoes may contribute to multiple physiological/pathological processes, while the contribution of others still has not been fully elucidated.

Fig 2

Vesicle (v) and target (t) SNAREs reside on opposing membranes. (A) In response to stimulus the vesicle translocates near to the target membrane and the four SNARE domains associate. (B) A conformational change in the complex brings the membranes close together and (C) eventually leads to overcoming the energy barrier enabling (D) fusion of the membranes and release of granular contents. This model and the core SNARE machinery is ubiquitously expressed throughout eukaryotic cells.

Fig 3

SNARE complex specificity is conferred by the 50–60 amino acid SNARE motif. (A) Four SNARE motifs from each of the Qa, Qb, Qc and R families form a functional four-helical bundle, which drives membrane fusion. (B) The QabcR configuration of the zero layer itself is completely conserved between different cell types and species, with the structure of the 16 amino acids up- and down-stream considerably less well conserved.