Biology of Platelet Purinergic Receptors and Implications for Platelet Heterogeneity

Abstract

Platelets are small anucleated cells present only in mammals. Platelets mediate intravascular hemostatic balance, prevent interstitial bleeding, and have a major role in thrombosis. Activation of platelet purinergic receptors is instrumental in initiation of hemostasis and formation of the hemostatic plug, although this activation process becomes problematic in pathological settings of thrombosis. This review briefly outlines the roles and function of currently known platelet purinergic receptors (P1 and P2) in the setting of hemostasis and thrombosis. Additionally, we discuss recent novel studies on purinergic receptor distribution according to heterogeneous platelet size, and the possible implication of this distribution on hemostatic function.

Keywords: ADP; ATP; adenosine; platelets; purinergic receptors.

FIGURE 1

Distribution of purinergic receptor transcripts with known function in the entire platelet population vs. large and small platelets. Platelets are a heterogeneous population of various sizes. Large platelets are highly hemostatically active while small ones are known to be much less active in hemostasis (Thompson et al., 1984; Guthikonda et al., 2008). RNA sequencing studies shown in Table 1 suggest differential distribution of purinergic receptors across platelets of different sizes, providing a provocative hypothesis related to potential functional differences in hemostasis when activated by adenine nucleosides and nucleotides, depending on platelet size. Future protein studies will be needed to test this contention. P2X1 is a ligand-gated ion channel that requires binding of ATP for influx of calcium; the rest of the P2 and P1 receptors in platelets are G-protein-coupled receptors. Of note, with the sensitivity of the above method of detection, P2Y1 or A2bAR transcripts are not found in the small or large platelets; however, these receptors for ADP or adenosine (respectively) are detected in the entire platelet population, suggesting a differential expression level in different platelet populations, possibly necessary for an extra layer of control over platelet function. These findings further encourage future examination of the receptors at protein and functional levels in different platelet populations. It is not known, however, if all of the purinergic receptors depicted in the top (or bottom) panel can be expressed on the same platelet, if there is differential signature of co-expression or if there is a mix of both of these possibilities. Ado, adenosine; ATP, adenosine triphosphate; ADP, adenosine diphosphate; cAMP, cyclic adenosine monophosphate; AC, adenylate cyclase.