Abstract
Inwardly-rectifying potassium (Kir) channels contribute to maintenance of the resting membrane potential and regulation of electrical excitation in many cell types. Strongly rectifying Kir channels exhibit a very steep voltage dependence resulting in silencing of their activity at depolarized membrane voltages. The mechanism underlying this steep voltage dependence is blockade by endogenous polyamines. These small multifunctional, polyvalent metabolites enter the long Kir channel pore from the intracellular side, displacing multiple occupant ions as they migrate to a stable binding site in the transmembrane region of the channel. Numerous structure-function studies have revealed structural elements of Kir channels that determine their susceptibility to polyamine block, and enable the steep voltage dependence of this process. In addition, various channelopathies have been described that result from alteration of the polyamine sensitivity or activity of strongly rectifying channels. The primary focus of this article is to summarize current knowledge of the molecular mechanisms of polyamine block, and provide some perspective on lingering uncertainties related to this physiologically important mechanism of ion channel blockade. We also briefly review some of the important and well understood physiological roles of polyamine sensitive, strongly rectifying Kir channels, primarily of the Kir2 family.
Highlights
Inward rectifiers and their regulation by endogenous polyaminesThis deviation from the outward current rectification observed for the classical “Hodgkin-Huxley” delayed rectifier potassium conductance led to the term “anomalous rectifier” in early literature describing ionic conductances ( known to be Kir channels) with strong inward rectification (Hutter and Noble, 1960)
In contrast to voltage gated potassium channels, which require membrane depolarization to open, strongly rectifying Kir channels remain active around the physiological resting membrane potential, and sharply diminish their activity upon membrane depolarization (Nichols and Lopatin, 1997; Lu, 2004; Hibino et al, 2010). This deviation from the outward current rectification observed for the classical “Hodgkin-Huxley” delayed rectifier potassium conductance led to the term “anomalous rectifier” in early literature describing ionic conductances with strong inward rectification (Hutter and Noble, 1960)
By “extrinsic,” we mean that the strength of inward rectification can be reduced or even completely abolished when these channels are removed from the cellular environment
Summary
This deviation from the outward current rectification observed for the classical “Hodgkin-Huxley” delayed rectifier potassium conductance led to the term “anomalous rectifier” in early literature describing ionic conductances ( known to be Kir channels) with strong inward rectification (Hutter and Noble, 1960) This unusual voltage dependence relative to most other ion channel types underlies the general functional role of strongly rectifying Kir channels, to contribute a significant potassium conductance when cells are not electrically excited and rapidly silence their activity in response to a depolarizing stimulus.
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