Inward Rectification of TWIK-1 Two-Pore Domain K+ Channels

Abstract

Mammalian two-pore domain K+ channels (K2P) mediate background K+ conductance and play an important role in regulation of cellular excitability and electrolyte homeostasis. TWIK-1 (also known as K2P1), the first cloned mammalian K2P channel, is highly expressed in the brain, kidney, and heart. They contribute to a large passive K+ conductance in rat hippocampal astrocytes, conduct inward leak Na+ currents in human cardiac myocytes under pathological hypokalemia, and regulate phosphate and water transport in mouse proximal tubule and medullary collecting duct, respectively. TWIK-1 K+ channels were first characterized in Xenopus oocytes and defined as weakly inward rectifying K+ channels. However, whether TWIK-1 K+ channels show inward rectification is contradictory, as several reports indicate that TWIK-1 K+ channels do not exhibit weakly inward rectification when expressed in mammalian cells and Xenopus oocytes. Here we report that TWIK-1 K+ channels heterologusly expressed in Chinese hamster ovary cells show weakly inward rectification in physiological K+ gradients. Such a rectification is caused by voltage-dependent blockade of intracellular blockers rather than rapid fast inactivation, as intracellular blockers bind to TWIK-1-specific sites in the inner pore of TWIK-1 K+ channels. These results improve current understandings of the function of TWIK-1 K+ channels as well as their contributions to cellular behaviors.