Abstract
Membrane phospholipids can function as potent regulators of ion channel function. This study uncovers and investigates the effect of phosphatidic acid on Kv channel gating. Using the method of reconstitution into planar lipid bilayers, in which protein and lipid components are defined and controlled, we characterize two effects of phosphatidic acid. The first is a non-specific electrostatic influence on activation mediated by electric charge density on the extracellular and intracellular membrane surfaces. The second is specific to the presence of a primary phosphate group, acts only through the intracellular membrane leaflet and depends on the presence of a particular arginine residue in the voltage sensor. Intracellular phosphatidic acid accounts for a nearly 50 mV shift in the midpoint of the activation curve in a direction consistent with stabilization of the voltage sensor's closed conformation. These findings support a novel mechanism of voltage sensor regulation by the signaling lipid phosphatidic acid.
Highlights
Voltage-gated potassium (Kv) channels shape and terminate action potentials
Phosphatidic acid is present in many cellular membranes including the inner leaflet of the plasma membrane where it plays essential roles in cellular pathways such as mTOR complex stability and signaling, growth factor receptor signaling and hormone signaling (Garrido et al, 2009)
PA can be rapidly depleted from the plasma membrane by phosphatidic acid phosphatase or a variety of phospholipases, allowing tight cellular control over its abundance (Foster, 2013)
Summary
Voltage-gated potassium (Kv) channels shape and terminate action potentials. While membrane voltage is the fundamental stimulus for Kv channel gating, other stimuli such as protein phosphorylation (Vacher and Trimmer, 2011), intracellular Ca2+ (Gamper et al, 2005) and accessory proteins regulate various Kv channels.In retrospect, given the lipid complexity of cell membranes, it is not surprising to learn that specific lipid molecules are among the regulators of membrane proteins generally and ion channels (Hilgemann et al, 2001; Dart, 2010). Even the structurally simple bacterial K+ channel KcsA requires anionic phospholipids in order to open (Heginbotham et al, 1998), while the more complex eukaryotic inward rectifier K+ channels are so dependent on the lipid PIP2 (see abbreviations section for lipid and detergent definitions) that they might have been called the PIP2-regulated K+ channels (Huang et al, 1998; Suh and Hille, 2005; Hansen et al, 2011; Whorton and MacKinnon, 2011) These are just two examples from a growing list of ion channels whose function depends on the presence of specific lipid molecules. Since PIP2 levels vary as a function of the physiological state of a cell, PIP2 is known as a ‘signaling lipid’ because it triggers or signals the action of molecules to which it binds, such as inward rectifier K+ channels
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