Role of lysophosphatidic acid in ion channel function and disease

Lysophosphatidic acid (LPA) is a bioactive phospholipid that exhibits a wide array of functions that include regulation of protein synthesis and adequate development of organisms. LPA is present in the membranes of cells and in the serum of several mammals and has also been shown to participate importantly in pathophysiological conditions. For several decades it was known that LPA produces some of its effects in cells through its interaction with specific G protein-coupled receptors, which in turn are responsible for signaling pathways that regulate cellular function. Among the target proteins for LPA receptors are ion channels that modulate diverse aspects of the physiology of cells and organs where they are expressed. However, recent studies have begun to unveil direct effects of LPA on ion channels, highlighting this phospholipid as a direct agonist and adding to the knowledge of the field of lipid-protein interactions. Moreover, the roles of LPA in pathophysiological conditions associated with the function of some ion channels have also begun to be clarified, and molecular mechanisms have been identified. This review focuses on the effects of LPA on ion channel function under normal and pathological conditions and highlights our present knowledge of the mechanisms by which it regulates the function and expression of N- and T-type Ca⁺⁺ channels; M-type K⁺ channel and inward rectifier K⁺ channel subunit 2.1; transient receptor potential (TRP) melastatin 2, TRP vanilloid 1, and TRP ankyrin 1 channels; and TWIK-related K⁺ channel 1 (TREK-1), TREK-2, TWIK-related spinal cord K⁺ channel (TRESK), and TWIK-related arachidonic acid-stimulated K⁺ channel (TRAAK).