Activation of Lysophosphatidic Acid Receptor Is Coupled to Enhancement of Ca<SUP>2＋</SUP>-Activated Potassium Channel Currents

Activation of Lysophosphatidic Acid Receptor Is Coupled to Enhancement of Ca<SUP>2＋</SUP>-Activated Potassium Channel Currents

The calcium-activated K^＋ (BK_Ca) channel is one of the potassium-selective ion channels that are present in the nervous and vascular systems. Ca^2＋ is the main regulator of BK_Ca channel activation. The BK_Cachannel contains two high affinity Ca^2＋ binding sites, namely, regulators of K^＋ conductance, RCK1 and the Ca^2＋ bowl. Lysophosphatidic acid (LPA, 1-radyl-2-hydroxy-sn-glycero-3-phosphate) is one of the neurolipids. LPA affects diverse cellular functions on many cell types through G protein- coupled LPA receptor subtypes. The activation of LPA receptors induces transient elevation of intracellular Ca^2＋ levels through diverse G proteins such as G&#1345;_q/11, G&#1345;_i, G&#1345;_12/13, and G&#1345;s and the related signal transduction pathway. In the present study, we examined LPA effects on BK_Cachannel activity expressed in Xenopus oocytes, which are known to endogenously express the LPA receptor. Treatment with LPA induced a large outward current in a reversible and concentration-dependent manner. However, repeated treatment with LPA induced a rapid desensitization, and the LPA receptor antagonist Ki16425 blocked LPA action. LPA-mediated BK_Ca channel activation was also attenuated by the PLC inhibitor U-73122, IP₃inhibitor 2-APB, Ca^2＋ chelator BAPTA, or PKC inhibitor calphostin. In addition, mutations in RCK1 and RCK2 also attenuated LPA-mediated BK_Ca channel activation. The present study indicates that LPA-mediated activation of the BK_Ca channel is achieved through the PLC, IP₃, Ca^2＋, and PKC pathway and that LPA-mediated activation of the BK_Ca channel could be one of the biological effects of LPA in the nervous and vascular systems.