Proposed mechanisms for P2-receptor–dependent activation of nonselective cation channels in the megakaryocyte and platelet. ADP activates an Na⁺- and Ca²⁺-permeable cation channel, likely to be a member of the TRP family of ion channels, by combined stimulation of P2Y₁ and P2Y₁₂ receptors. (1) P2Y₁ activation of PLCβ hydrolyzes PIP₂, resulting in the removal of an inhibitory action on the cation channel. (2) Simultaneously, P2Y₁₂ activates PI3-kinase by its Gβγ subunits, resulting in the phosphorylation of PIP₂ to PIP₃, further decreasing the inhibition by PIP₂. (3) PIP₃ may be an activator of this or another cation channel.⁶⁰  (4) Both diacylglycerol (DAG) and IP₃ (or an IP₃ metabolite) have been reported to activate cation channels in the platelet/MK.^26,28,29,48  IP₃ results in the release of stored Ca²⁺, which further modulates the cation channel.²⁶  (5) P2Y₁₂ receptors, through PI3-kinase, stimulate dense granule release into the open canalicular system in the platelet/demarcation membrane system in the MK (OCS/DMS); P2Y₁-dependent protein kinase C (PKC) stimulation is also likely to potentiate this secretion. (6) Released ATP can repetitively activate P2X₁ receptors and further modulate the P2Y current through Ca²⁺ influx. MLCK indicates myosin light-chain kinase.