Genetic defects in the hotspot of inwardly rectifying K(+) (Kir) channels and their metabolic consequences: a review

Abstract

Inwardly rectifying potassium (Kir) channels are essential for maintaining normal potassium homeostasis and the resting membrane potential. As a consequence, mutations in Kir channels cause debilitating diseases ranging from cardiac failure to renal, ocular, pancreatic, and neurological abnormalities. Structurally, Kir channels consist of two trans-membrane domains, a pore-forming loop that contains the selectivity filter and two cytoplasmic polar tails. Within the cytoplasmic structure, clusters of amino acid sequences form regulatory domains that interact with cellular metabolites to control the opening and closing of the channel. In this review, we present an overview of Kir channel function and recent progress in the characterization of selected Kir channel mutations that lie in and near a C-terminal cytoplasmic 'hotspot' domain. The resultant molecular mechanisms by which the loss or gain of channel function leads to organ failure provide potential opportunities for targeted therapeutic interventions for this important group of channelopathies.

Figure 1. Kir channel topology

The predicted amino acid positions of the cytoplasmic, trans-membrane, and extracellular domains of the selected Kir channel subunits. The membrane topology illustrating the localization of two cytoplasmic (N and C terminal), two trnasmembrane (M1 and M2), and extracellular GYG selectivity loop with reference to plasma-membrane is represented. The cytoplasmic ‘hotspot’ is highlighted with sequence homology amongst human Kir channels compared. Highlighted aminoacids within and nearby the ‘hotspot’ are shown that represent disease-causing mutations.

Figure 2. Inward rectification properties of Kir channels

Current amplitude in response to membrane voltage is shown by representative current-voltage (I–V) relationships of Kir channels with both strong inward rectifiers (A. aqua trace), or mild inward rectifiers illustrated (A. dark red trace). Current in the negative direction (inward current) is indicated by a downward arrow and current in the positive direction is the outward current. For strong inward rectifiers, the outward current is completely blocked by intracellular factors affecting the I–V relationship as compared to the persistent outward current demonstrated by mild inward rectifiers. B) I–V relationship model of a mildly inward rectifier channel (B. dark red trace, as in A.) showing predicted changes in both inward and outward current due to either a gain-of-function (B. green trace) or loss-of-function (B. red trace) due to genetic mutation(s).

Figure 3. Tissue distribution of Kir channel subunits

The tissue-specific distribution of the Kir channels suggests that they play an important role in ion homeostasis and disease. Kir channel subunits are indicated by light blue within the membrane structure. All other possible associated channels, transporters and regulatory molecules are also shown in the membrane that controls cellular physiology. Kir channels tissue distribution along with their respective physiopathology are color-coded (Kir1.1- orange; Kir2.1- blue; Kir4.1- purple; Kir6.2- green and Kir7.1- red). Abbreviations: Kir, inwardly rectifying potassium channel; SUR, regulatory suramine subunit; ATP, adenosine tri-phosphate; ADP, adenosine di-phosphate; RPE, retinal pigment epithelium; PIP₂, phosphatidylinositol (4,5)-bisphosphate; TAL, thick ascending limb.