Potassium–dependent activation of Kir4.2 K+ channels

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Abstract

Non–technical summary

The inwardly rectifying potassium channel, Kir4.2, is amongst the members of the Kir family of K+ channels whose activity is directly regulated by the external potassium concentration. We show here that, rather than increasing expression of the channel protein, this regulation is accomplished by activation of silent channels already present at the cell surface. Understanding the mechanism of this regulation will aid in understanding the physiological processes in which this subset of K+ channels is involved, such as regulation of blood pressure and control of neuronal excitability. It may also help to explain some of the consequences of hyperkalaemia, or excessive potassium, in blood plasma.

The inwardly rectifying potassium channel Kir4.2 is sensitive to changes in the extracellular potassium concentration ([K+]o). This form of regulation is manifest as a slow (tens of minutes) increase in the whole–cell currents when [K+]o is increased. Here we have investigated the mechanism of Symbol sensitivity of Kir4.2 expressed in Xenopus oocytes. Using two–electrode voltage clamp we found that the Symbol sensitivity is specific for the homomeric form of the channel and is completely abolished when coexpressed with Kir5.1. Furthermore, unlike Kir1.1, there is no coupling between the intracellular pH sensitivity and Symbol sensitivity, as is evident by introducing a mutation (K66M), which greatly decreases the pHi sensitivity while the Symbol sensitivity remains unchanged. Symbol–dependent activation of Kir4.2 does not involve an increase in the surface expression of the channel, nor is there a difference in the open probability between high and low [K+] as determined through patch–clamp measurements. We also found that there is an inverse relationship between the rates of both activation and deactivation and [K+]o. Using a kinetic model we argue that Kir4.2 exists in at least three states at the plasma membrane: a deactivated state, an intermediate unstable state and an active state, and that [K+]o affects the rate of transition from the intermediate state to the active state.

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