The unique structural characteristics of the Kir 7.1 inward rectifier potassium channel: a novel player in energy homeostasis control

Abstract

The inward rectifier potassium channel Kir7.1, encoded by the Kcnj13 gene, is a tetramer composed of two-transmembrane domain-spanning monomers, closer in homology to Kir channels associated with potassium transport such as Kir1.1, 1.2, and 1.3. In comparison to other channels, Kir7.1 exhibits small unitary conductance and low dependence on external potassium. Kir7.1 channels also show a phosphatidylinositol 4,5-bisphosphate (PIP2) dependence for opening. Accordingly, retinopathy-associated Kir7.1 mutations mapped at the binding site for PIP2 resulted in channel gating defects leading to channelopathies such as snowflake vitreoretinal degeneration and Leber congenital amaurosis in blind patients. Lately, this channel's role in energy homeostasis was reported due to the direct interaction with the melanocortin type 4 receptor (MC4R) in the hypothalamus. As this channel seems to play a multipronged role in potassium homeostasis and neuronal excitability, we will discuss what is predicted from a structural viewpoint and its possible implications for hunger control.

Novel Cocrystal Structures of Peptide Antagonists Bound to the Human Melanocortin Receptor 4 Unveil Unexplored Grounds for Structure-Based Drug Design

“…None of the control (i.e., α-MSH, SHU9119 , or AgRP) or the test peptides elicited a response (data not shown). This duality of effects highlights the modular and independent receptor conformational states required for G protein recruitment and activation versus channel complexing in the open and closed states. , …”

“…Elevation in blood pressure is another significant adverse effect affecting drug candidates targeting the melanocortin system . With the discovery of the G protein-independent modulation of Kir7.1 by MC4-R, ,, a new window of opportunity has opened by targeting the MC4-R:Kir7.1 complex while potentially avoiding G protein signaling-associated side effects. The duality of effects on channel activity of the peptides generated for this study highlights the independence of the allosteric mechanisms that operate to couple active receptors with G s protein signaling and channel activity coupling (Figures A,B, S9, and S10).…”

“…The ideal melanocortin drug for treating restrictive eating disorders would display high antagonist potency for MC4-R, high selectivity for MC4- over MC3-R, and channel activator activity by targeting the MC4-R:Kir7.1 complex. ,, As the chemical space explored with this peptide series did not significantly feature MC4- over MC3-R selectivity (Figure B), it would be expected that a three-variable correlation of MC4-R antagonist potency versus MC3-R selectivity and MC4-R:Kir7.1 coupling would fail to expose the negative effect of MC3-R selective antagonist activity about the orexigenic impact observed for SBL-MC-93 in contrast to the anorexigenic effect recorded for SBL-MC-78 in vivo (note both peptides occupying the same quadrant on the graph depicted in Figure ). Confirmation of this corollary will require further investigation of the switches that control MC3-R agonist actions while preserving MC4-R antagonist and Kir7.1 activator activities.…”

“…Control or test peptides were delivered at various concentrations across the NPC-384 chip. Ten micromolar (final) test peptide followed by a Ba 2+ full channel block was added to each well to determine non-K + channel currents as the M125R Kir7.1 regains sensitivity for Ba 2+ as opposed to the relatively insensitive wild-type Kir7.1 . The responses were further normalized by determining the ratios of peak currents in the presence or absence of test peptides ( I compound / I 0 ).…”

“…Kir7.1, an inwardly rectifying potassium channel expressed in several tissues within and outside the central nervous system, including the PVH. 67,68 Conditional ablation of Kcnj13, the gene encoding Kir7.1 in PVH MC4R neurons, resulted in impaired α-MSH-induced depolarization of this neuronal population as determined by loose-patch current clamp recordings in ex vivo slice preparations. 69 In cells coexpressing MC4-R and Kir7.1 where the receptor third intracellular loop was deleted, AgRP induced increased Kir7.1-mediate K + currents.…”