Sodium-hydrogen exchange and platelet function

On stimulation of platelets with agonists, for example, thrombin, a rapid r ise in intracellular pH is observed. This alkalinization is mediated by an increase in transport activity of the Na+/H+ exchanger isoform NHE1. In add ition to this Na+/H+ exchange mechanism, platelets express bicarbonate/chlo ride exchangers, which also contribute to pH(i) homeostasis. The main funct ions of NHE1 in platelets include pH(i) control, volume regulation, and par ticipation in cell signaling. The isoform NHE1 is highly sensitive toward i nhibition by EIPA, Hoe694, and Hoe642. The regulation of NHE1 activity is c omplex and is not completely understood. It includes the MAP kinase cascade , the Ca/calmodulin system, several heterotrimeric G proteins (G alpha 12, G alpha 13, G alpha q, and G alpha i), small G proteins (ras, cdc42, rhoA), and downstream kinases (e.g., p160ROCK). Volume challenges stimulate tyros ine phosphorylation of cytoplasmic proteins, which ultimately activate NHE1 . Thrombin, thromboxane, platelet-activating factor, angiotensin II, endoth elin, phorbol ester, and Ca2+ ionophors stimulate NHE1 activity in platelet s. Blockade of platelet NHE1 can inhibit platelet activation. With the deve lopment of highly specific NHE1 inhibitors, detailed investigation of the r elationships between NHE1 activity and platelet activation now becomes feas ible.