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Kir4.1 K+ channels are regulated by external cations.

ABSTRACT: The inwardly rectifying potassium channel (Kir), Kir4.1 mediates spatial K(+)-buffering in the CNS. In this process the channel is potentially exposed to a large range of extracellular K(+) concentrations ([K(+)]o). We found that Kir4.1 is regulated by K(+)o. Increased [K(+)]o leads to a slow (mins) increase in the whole-cell currents of Xenopus oocytes expressing Kir4.1. Conversely, removing K(+) from the bath solution results in a slow decrease of the currents. This regulation is not coupled to the pHi-sensitive gate of the channel, nor does it require the presence of K67, a residue necessary for K(+)o-dependent regulation of Kir1.1. The voltage-dependent blockers Cs(+) and Ba(2+) substitute for K(+) and prevent deactivation of the channel in the absence of K(+)o. Cs(+) blocks and regulates the channel with similar affinity, consistent with the regulatory sites being in the selectivity-filter of the channel. Although both Rb(+) and NH4(+) permeate Kir4.1, only Rb(+) is able to regulate the channel. We conclude that Kir4.1 is regulated by ions interacting with specific sites in the selectivity filter. Using a kinetic model of the permeation process we show the plausibility of the channel's sensing the extracellular ionic environment through changes in the selectivity occupancy pattern, and that it is feasible for an ion with the selectivity properties of NH4(+) to permeate the channel without inducing these changes.

SUBMITTER: Edvinsson JM

PROVIDER: S-EPMC3225756 | biostudies-literature | 2011 May-Jun

REPOSITORIES: biostudies-literature

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Kir4.1 K+ channels are regulated by external cations.

Edvinsson Johan M JM Shah Anish J AJ Palmer Lawrence G LG

Channels (Austin, Tex.) 20110501 3

The inwardly rectifying potassium channel (Kir), Kir4.1 mediates spatial K(+)-buffering in the CNS. In this process the channel is potentially exposed to a large range of extracellular K(+) concentrations ([K(+)]o). We found that Kir4.1 is regulated by K(+)o. Increased [K(+)]o leads to a slow (mins) increase in the whole-cell currents of Xenopus oocytes expressing Kir4.1. Conversely, removing K(+) from the bath solution results in a slow decrease of the currents. This regulation is not coupled t ...[more]

PMID: 21532341

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Project description:All inhalation anesthetics used clinically including isoflurane can suppress breathing; since this unwanted side effect can persist during the postoperative period and complicate patient recovery, there is a need to better understand how isoflurane affects cellular and molecular elements of respiratory control. Considering that astrocytes in a brainstem region known as the retrotrapezoid nucleus (RTN) contribute to the regulation of breathing in response to changes in CO2/H+ (i.e., function as respiratory chemoreceptors), and astrocytes in other brain regions are highly sensitive to isoflurane, we wanted to determine whether and how RTN astrocytes respond to isoflurane. We found that RTN astrocytes in slices from neonatal rat pups (7-12 days postnatal) respond to clinically relevant levels of isoflurane by inhibition of a CO2/H+-sensitive Kir4.1/5.1-like conductance [50% effective concentration (EC50) = 0.8 mM or ~1.7%]. We went on to confirm that similar levels of isoflurane (EC50 = 0.53 mM or 1.1%) inhibit recombinant Kir4.1/5.1 channels but not homomeric Kir4.1 channels expressed in HEK293 cells. We also found that exposure to CO2/H+ occluded subsequent effects of isoflurane on both native and recombinant Kir4.1/5.1 currents. These results identify Kir4.1/5.1 channels in astrocytes as novel targets of isoflurane. These results suggest astrocyte Kir4.1/5.1 channels contribute to certain aspects of general anesthesia including altered respiratory control.NEW & NOTEWORTHY An unwanted side effect of isoflurane anesthesia is suppression of breathing. Despite this clinical significance, effects of isoflurane on cellular and molecular elements of respiratory control are not well understood. Here, we show that isoflurane inhibits heteromeric Kir4.1/5.1 channels in a mammalian expression system and a Kir4.1/5.1-like conductance in astrocytes in a brainstem respiratory center. These results identify astrocyte Kir4.1/5.1 channels as novel targets of isoflurane and potential substrates for altered respiratory control during isoflurane anesthesia.

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Kir4.1 K+ channels are regulated by external cations.

Publications

Kir4.1 K+ channels are regulated by external cations.

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