Activation of Lysophosphatidic Acid Receptor Is Coupled to Enhancement of Ca(2+)-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(Ca) channel 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 Gα(q/11), Gα(i), Gα(12/13), and Gαs and the related signal transduction pathway. In the present study, we examined LPA effects on BK(Ca) channel 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, IP(3) inhibitor 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, IP(3), 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.