Potassium leak channels and the KCNK family of two-p-domain subunits

• Published in: Nature reviews. Neuroscience Vol. 2; no. 3; pp. 175 - 184
• Main Authors: Goldstein, Steve A. N., Bockenhauer, Detlef, O'Kelly, Ita, Zilberberg, Noam
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2001; Nature Publishing Group
• Subjects: Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Electrophysiology; Equilibrium; Genes; Humans; Models, Molecular; Myocardium - metabolism; Nerve Tissue Proteins; Neurobiology; Neurons - metabolism; Neurosciences; Oocytes - physiology; Patch-Clamp Techniques; Physiology; Potassium; Potassium - metabolism; Potassium Channels - chemistry; Potassium Channels - genetics; Potassium Channels - physiology; Potassium Channels, Tandem Pore Domain; Protein Conformation; Protein Structure, Tertiary; Protein Subunits; review-article
• ISSN: 1471-003X; 1471-0048; 1471-0048; 1469-3178
• DOI: 10.1038/35058574

With a bang, a new family of potassium channels has exploded into view. Although KCNK channels were discovered only five years ago, they already outnumber other channel types. KCNK channels are easy to identify because of their unique structure — they possess two pore-forming domains in each subunit. The new channels function in a most remarkable fashion: they are highly regulated, potassium-selective leak channels. Although leak currents are fundamental to the function of nerves and muscles, the molecular basis for this type of conductance had been a mystery. Here we review the discovery of KCNK channels, what has been learned about them and what lies ahead. Even though two-P-domain channels are widespread and essential, they were hidden from sight in plain view — our most basic questions remain to be answered. Key Points 50 years after leak currents were first described, potassium-selective leak channels have been found —the KCNK channel family. KCNK channels are numerous and widespread. The genes encode unique channel subunits with two pore-forming P domains. Whereas fungi and plants contain variants that operate as non-voltage dependent outward rectifiers, animals have at least 50 genes for the KCNK channels that function as open rectifiers by primarily passing outward current under physiological potassium concentrations. Studies of single KCNK channels have confirmed that leak currents result from channels open at rest and have shown that leak channels are not always open. Instead, like their native counterparts, KCNK channels are subject to strict regulation by second messenger systems. KCNK channels seem to control the excitability of nerves and heart, and perhaps to mediate the effects of volatile anaesthetics. So, neurotransmitter-mediated inhibition of resting potassium flux has an excitatory influence, whereas increased activity with anaesthetic exposure stabilizes cells at rest. Regulation of one KCNK isolate has been observed to reversibly produce leak or voltage-dependent function, modes that stabilize cells and facilitate repetitive excitation, respectively. This significantly expands the functional spectrum of KCNK channels. Many questions regarding KCNK channels remain to be answered. Where are their gates and do they resemble the gates of one-P-domain channels? Do two-P-domain channels function as dimers? Do both pore domains contribute directly to pore formation? Do KCNK subunits form heteromers? What roles do KCNK channels play in health and disease?