Abstract
Atherothrombosis, the pathology underlying numerous cardiovascular diseases, is a major cause of death globally. Hyperactive blood platelets play a key role in the atherothrombotic process through the release of inflammatory mediators and formation of thrombi. In healthy blood vessels, excessive platelet activation is restricted by endothelial-derived prostacyclin (PGI2) through cyclic adenosine-5′-monophosphate (cAMP) and protein kinase A (PKA)-dependent mechanisms. Elevation in intracellular cAMP is associated with the control of a number of distinct platelet functions including actin polymerisation, granule secretion, calcium mobilization and integrin activation. Unfortunately, in atherosclerotic disease the protective effects of cAMP are compromised, which may contribute to pathological thrombosis. The cAMP signaling network in platelets is highly complex with the presence of multiple isoforms of adenylyl cyclase (AC), PKA, and phosphodiesterases (PDEs). However, a precise understanding of the relationship between specific AC, PKA, and PDE isoforms, and how individual signaling substrates are targeted to control distinct platelet functions is still lacking. In other cells types, compartmentalisation of cAMP signaling has emerged as a key mechanism to allow precise control of specific cell functions. A-kinase anchoring proteins (AKAPs) play an important role in this spatiotemporal regulation of cAMP signaling networks. Evidence of AKAP-mediated compartmentalisation of cAMP signaling in blood platelets has begun to emerge and is providing new insights into the regulation of platelet function. Dissecting the mechanisms that allow cAMP to control excessive platelet activity without preventing effective haemostasis may unleash the possibility of therapeutic targeting of the pathway to control unwanted platelet activity.
Highlights
Blood platelets play a key role in haemostasis through binding to sites of vascular injury to form a primary haemostatic plug
Primary inhibitory mechanisms are mediated by endothelial derived-nitric oxide (NO) and prostacyclin (PGI2), which stimulate soluble guanylyl cyclase and adenylyl cyclase (AC) leading to activation of cyclic guanosine monophosphate and cyclic adenosine monophosphatemediated signaling pathways, respectively (Smolenski, 2012). cAMP/cGMP-dependent protein cAMP signaling in blood platelets kinases phosphorylate target proteins that are associated with controlling platelet activation while multiple phosphodiesterases (PDEs) hydrolyse cyclic nucleotides to terminate signaling
Given the central importance of cAMP signaling to the control of platelet function, surprisingly little is known about the molecular mechanisms that coordinate the synthesis and hydrolysis of cAMP, the precise molecular targets of cAMP signaling and how these targets contribute to the control of specific platelet functions
Summary
Blood platelets play a key role in haemostasis through binding to sites of vascular injury to form a primary haemostatic plug. In many cell types the enzymes that generate, propagate and terminate cAMP signaling are organized into restricted microdomains that focus the activity of the cAMP signaling cascade to specific substrates (Tasken and Aandahl, 2004; Scott and Pawson, 2009; Stangherlin and Zaccolo, 2012) This compartmentalisation of cAMP signaling allows stimulusspecific control of distinct cell functions. Given the central importance of cAMP signaling to the control of platelet function, surprisingly little is known about the molecular mechanisms that coordinate the synthesis and hydrolysis of cAMP, the precise molecular targets of cAMP signaling and how these targets contribute to the control of specific platelet functions. We provide an overview of cAMP signaling and examine emerging concepts of compartmentalization in platelets
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