ABSTRACT
Kv4/K channel interacting protein (KChIP) potassium channels are a major class of rapidly inactivating K(+) channels in neurons and cardiac muscle. Modulation of Kv4/KChIP channels by polyunsaturated fatty acids (PUFAs) is important in the regulation of cellular excitability and the induction of activity-dependent synaptic plasticity. Using the Xenopus laevis oocyte expression system, we studied the inhibition by PUFAs of the peak outward K(+) current and the accompanying increase in the rate of current inactivation of rKv4.2/rKChIP1b. Inhibitory effects do not depend on KChIP coexpression since Kv4.2 channels lacking an NH(2)-terminal KChIP association region were substantially inhibited by PUFAs and showed strong kinetic modulation. PUFAs accelerated both the fast and slow time constants that describe the kinetics of Kv4/KChIP inactivation. The time course of entry into closed inactivated states was facilitated by PUFAs, but steady-state inactivation and recovery from inactivation were unaltered. PUFA inhibition of Kv4/KChIP current was not use dependent. The concentration-response relationship for arachidonic acid (AA) inhibition of Kv4/KChIP channels mimicked that for activation of TRAAK channels. Internal serum albumin largely prevents the inhibitory effects of externally applied AA, and the membrane-impermeant AA-CoA is inactive when applied externally. Overall, our data suggest that PUFAs inhibit Kv4/KChIP channels by facilitating inactivation from open and closed gating states and that access of the fatty acid to the internal leaflet of the membrane is important. These results improve our understanding of the mechanisms for the inhibitory effects of PUFAs on Kv4/KChIP channel function.
Subject(s)
Fatty Acids, Unsaturated/pharmacology , Ion Channel Gating/drug effects , Kv Channel-Interacting Proteins/metabolism , Shal Potassium Channels/genetics , Shal Potassium Channels/metabolism , Animals , Arachidonic Acid/pharmacology , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Fatty Acids, Unsaturated/metabolism , Female , Gene Expression/physiology , Humans , Ion Channel Gating/physiology , Kv Channel-Interacting Proteins/genetics , Mice , Nerve Tissue Proteins/genetics , Neuronal Plasticity/physiology , Oocytes/physiology , Patch-Clamp Techniques , Plasmids , Potassium/metabolism , Potassium Channels/genetics , Rats , Serum Albumin/pharmacology , Xenopus laevisABSTRACT
Arachidonic acid (AA) was found to inhibit the function of whole-cell voltage-gated (VG) calcium currents nearly 16 years ago. There are now numerous examples demonstrating that AA and other polyunsaturated fatty acids (PUFAs) modulate the function of VG ion channels, primarily in neurons and muscle cells. We will review and extract some common features about the modulation by PUFAs of VG calcium, sodium, and potassium channels and discuss the impact of this modulation on the excitability of neurons and cardiac myocytes. We will describe the fatty acid nature of the membrane, how fatty acids become available to function as modulators of VG channels, and the physiologic importance of this type of modulation. We will review the evidence for molecular mechanisms and assess our current understanding of the structural basis for modulation. With guidance from research on the structure of fatty acid binding proteins, the role of lipids in gating mechanosensitive (MS) channels, and the impact of membrane lipid composition on membrane-embedded proteins, we will highlight some avenues for future investigations.
