P2Y₁₄ receptor activation of platelets induces Ca²⁺ mobilization and Rho-GTPase-dependent motility that requires an interaction with P2Y₁ receptors

TY - JOUR

T1 - P2Y14 receptor activation of platelets induces Ca2+ mobilization and Rho-GTPase-dependent motility that requires an interaction with P2Y1 receptors

AU - Hossain, Md Monir

AU - Pan, Dingxin

AU - Arkless, Kate L.

AU - Rahman, Khondaker Miraz

AU - Page, Clive P.

AU - Authi, Kalwant S.

AU - Pitchford, Simon C.

N1 - Publisher Copyright: © 2025 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

PY - 2025/2/18

Y1 - 2025/2/18

N2 - Background and Purpose: Platelet function during inflammation is dependent on activation by endogenous nucleotides acting on purinergic receptors. The P2Y14 receptor has been reported to be expressed on platelets and is involved in leukocyte recruitment during inflammation. However, a role for P2Y14 receptors in platelet function has not yet been determined. Experimental Approach: Platelets obtained from healthy human volunteers were incubated with the P2Y14 receptor agonist, UDP-Glucose (UDP-G), and PPTN, a selective P2Y14 receptor antagonist. Platelet activation was quantified using Ca2+ mobilization, aggregation and chemotaxis assays. Cooperativity with P2Y1 receptor activation was also assessed after stimulation with UDP-G in the presence of MRS2500, a selective P2Y1 receptor antagonist. Key Results: Ca2+ mobilization occurred in platelets after incubation with UDP-G in a concentration-dependent manner, and this was suppressed in platelets treated with PPTN. Platelets did not aggregate, or bind to fibrinogen after incubation with UDP-G. However, platelet chemotaxis towards f-MLP was dependent on P2Y14 receptor stimulation with UDP-G and this was reduced by Rho-GTPase inhibitors. Furthermore, UDP-G-induced Ca2+ mobilization and chemotaxis were also inhibited when platelets were pretreated with MRS2500. Conversely, ADP-induced Ca2+ mobilization, chemotaxis and aggregation were not affected by the incubation with PPTN. Conclusion and Implications: Platelets can be activated via P2Y14 receptor stimulation to induce chemotaxis but not aggregation. Furthermore, this was dependent on concomitant activation of P2Y1 receptor. Activation of P2Y14 receptors on platelets may therefore be relevant during inflammation, but cooperation with P2Y1 receptor activation is required.

AB - Background and Purpose: Platelet function during inflammation is dependent on activation by endogenous nucleotides acting on purinergic receptors. The P2Y14 receptor has been reported to be expressed on platelets and is involved in leukocyte recruitment during inflammation. However, a role for P2Y14 receptors in platelet function has not yet been determined. Experimental Approach: Platelets obtained from healthy human volunteers were incubated with the P2Y14 receptor agonist, UDP-Glucose (UDP-G), and PPTN, a selective P2Y14 receptor antagonist. Platelet activation was quantified using Ca2+ mobilization, aggregation and chemotaxis assays. Cooperativity with P2Y1 receptor activation was also assessed after stimulation with UDP-G in the presence of MRS2500, a selective P2Y1 receptor antagonist. Key Results: Ca2+ mobilization occurred in platelets after incubation with UDP-G in a concentration-dependent manner, and this was suppressed in platelets treated with PPTN. Platelets did not aggregate, or bind to fibrinogen after incubation with UDP-G. However, platelet chemotaxis towards f-MLP was dependent on P2Y14 receptor stimulation with UDP-G and this was reduced by Rho-GTPase inhibitors. Furthermore, UDP-G-induced Ca2+ mobilization and chemotaxis were also inhibited when platelets were pretreated with MRS2500. Conversely, ADP-induced Ca2+ mobilization, chemotaxis and aggregation were not affected by the incubation with PPTN. Conclusion and Implications: Platelets can be activated via P2Y14 receptor stimulation to induce chemotaxis but not aggregation. Furthermore, this was dependent on concomitant activation of P2Y1 receptor. Activation of P2Y14 receptors on platelets may therefore be relevant during inflammation, but cooperation with P2Y1 receptor activation is required.

KW - aggregation

KW - Ca

KW - chemotaxis

KW - P2Y

KW - platelets

UR - http://www.scopus.com/inward/record.url?scp=105000626267&partnerID=8YFLogxK

U2 - 10.1111/bph.70024

DO - 10.1111/bph.70024

M3 - Article

AN - SCOPUS:105000626267

SN - 0007-1188

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

ER -