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Review
. 2023 Mar 1;324(3):C694-C706.
doi: 10.1152/ajpcell.00335.2022. Epub 2023 Jan 30.

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

Ciria C Hernandez  1 , Luis E Gimenez  1 , Naima S Dahir  1 , Alys Peisley  1 , Roger D Cone  1   2
Affiliations
Review

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

Ciria C Hernandez et al. Am J Physiol Cell Physiol. .

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. Compared with 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.

Keywords: energy homeostasis; inward rectifier potassium channel 13 (Kir7.1); melanocortin receptor 4; phosphatidylinositol 4,5-bisphosphate; single-nucleotide polymorphism.

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Conflict of interest statement

R. D. Cone and L. E. Gimenez have equity interests in Courage Therapeutics, Inc. and are inventors of intellectual property optioned to the company. R. D. Cone is a founder, board member, and SAB Chair of Courage Therapeutics, Inc. The other authors have no conflicts of interest, financial or otherwise, to disclose.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Inwardly rectifying K+ (Kir) channel structures. A: comparison of solved structures of the Kir3.1 prokaryotic chimeric channel (PDB: 2QKS), Kir2.2 complexed with PIP2 (PDB: 3SPI), Kir3.2 complexed with phosphatidylinositol 4,5-bisphosphate (PIP2) (PDB: 6XIT), and Kir6.2 (PDB: 7S5T) highlighting common structural domains. PIP2 molecules are rendered as sticks colored according to atom type, and K+ ions as purple spheres. B: Kir family member structural alignment illustrates the high conservation among functional domains. Tetrameric arrangement of the Kir structures at the G-loop (C) and selectivity filter (E) domains showing standard structural features viewed from the extracellular side. D: the side view of two opposing Kir subunits illustrates the structural conservation of the selectivity filter, PIP2 binding sites at the transmembrane domains (TMD)- cytoplasmic domain (CTD) interface, and the G-loop domain.
Figure 2.
Figure 2.
Inwardly rectifying K+ (Kir)7.1 structural determinants. A: cartoon of the phylogenetic tree of voltage-gated ion channel families and the branches belonging to the Kir family. The structural model of the Kir7.1 channel based on the Kir 2.2 structure (PDB: 3SPI) shows the tetrameric arrangement of the channel, viewed from the side (B) and an extracellular viewpoint (C). Phosphatidylinositol 4,5-bisphosphate (PIP2) molecules docked at their putative binding site, and K+ ions within the conducting pathway resemble the Kir2.2 structure (Fig. 1A). D: a ribbon representation of a structural model of a Kir7.1 monomer showing the conserved domains among all Kir structures. E: sequence alignment across the Kir family members illustrates the pore domain conservation. Highlighted in red are the residues at the selectivity filter (SF) motif, and in blue, M125, which determines Kir7.1 conductance. F: close-up view of the conserved motif of residues that line the conducting pathway at the selectivity filter (SF) and the position of the four K+ occupancies in the Kir7.1 model. G: close-up view of the putative PIP2 binding pocked in the Kir7.1 model. As PIP2 docket at the Kir2.2 homologous phosphoinositide binding site, homologous charged residues (labeled in black) share common interactions with the negatively charged phospholipid head of PIP2. The surface of the PIP2 molecule is shown as an electrostatically charged surface in panels B, C, and G. H: sequence alignment of the structural domains for the PIP2 binding site. Residues in red were reported to interact with PIP2 in Kir2.2, and residues in blue are the homologous predicted positions for Kir7.1.
Figure 3.
Figure 3.
Inwardly rectifying K+ (Kir)7.1 disease-causing mutations. A: the tolerance landscape for the entire protein-coding region of the Kir7.1 channel (KCNJ13 GENCODE: ENST00000233826.3, RefSeq: NM_002242.4, UniProt: O60928, domain: PF01007) based on the Genome Aggregation Database (gnomAD) variants ranges from highly intolerant (score of 0.12, red) to highly tolerant (score of 2.83, blue) positions. The tolerance score for KCNJ13 disease-causing mutations was as follows: position: p.117 c.349–351, residue: Gln, score: 0.36, intolerant; position: p.162 c.484–486, residue: Arg, score: 0.91, slightly tolerant: position: p.241 c.721–723, residue: Leu, score: 0.51, intolerant: position: p. 276 c.826–828, residue: Glu, score: 0.56, slightly intolerant. The disease Mendelian inheritance classification (omim.org) is noted below the KCNJ13 disease-causing mutation (see details in text). B: structural model of Kir7.1 mapping the KCNJ13 mutation sites (in steel blue), side view. PIP2 molecules are represented as translucent white surfaces (C and D). Extracellular views of the tetrameric structure model of Kir7.1 sliced at the pore (C) and inner helix (D) regions (red dashed lines in B) show Q117 appearing to be in a position to interact with T117 at the selectivity filter, R162, and E276 predicted to be in close interaction with the PIP2 binding site and within the G-loop respectively, and L241 at neighboring monomer interfaces in the CTD.
Figure 4.
Figure 4.
Inwardly rectifying K+ (Kir)7.1 variants. A: structural mapping of missense variants into a monomer within the Kir7.1 tetrameric model (left). The right panel shows a single Kir7.1 monomer mapping 210 missense variants for the KCNJ13 isoform NM_002242.4 (RefSeq Match) O60928-1 (UniProt ID) ENST00000233826.4 (Transcript ID). Missense variants are colored according to the structural domain and mapped onto the Kir7.1: N-cytoplasmic in gray, M1 in orange, turret I in yellow, H5-Pore helix in green, selectivity filter (SF) in red, turret II in white, M2 in blue, and C-cytoplasmic in purple. B: pathogenicity score heatmap for 210 missense variants using PolyPhen2 (line A), REVEL (line B), and MetaLR (line C). The pathogenicity scores ranged from 0 (tolerated/likely benign) to 1 (damaging/potential disease-causing). The 210 missense variants were sorted by Kir7.1 structural regions with linearized sequences shown as colored boxes on top of the heatmap. C: missense variant frequency distribution by structural domains and color-coded as earlier. D: occurrence of missense variants colored by residue property: aliphatic in gray, neutral in green, aromatic in purple, positive in blue, negative in red, Pro and Gly in white, and Cys in yellow. E: the occurrence of alternative residues (missense variant) found at each position in the sequence alignment of the Kir7.1 is shown. The color code for the 20 alternative residues is based on the residue property: aliphatic residues in shades of gray, neutral residues in shades of green, aromatic residues in shades of purple, positive residues in shades of blue, and negative residues in shades of red.
Figure 5.
Figure 5.
Basic arcuate nucleus of the hypothalamus (ARH) to paraventricular nucleus (PVH) neuronal circuit for the control of energy balance. ARHAgRP and ARHPOMC neurons receive energy balance cues from peripheral organs and relay this information to the PVH, including PVHMC4R neurons. The ARHPOMC neurons contribute primary anorexigenic inputs represented by the release of melanocyte-stimulating hormones (MSH) at the synaptic cleft level. In humans, α-MSH promotes postsynaptic melanocortin type 4 receptor (MC4R) activation resulting in PVHMC4R neuron increased firing frequency. In addition, direct MC4R-operated inwardly rectifying K+ (Kir)7.1 closure enables increased firing frequency by depolarizing the cell’s resting potential. Agouti-related peptide (AgRP) release and binding to postsynaptic MC4R results in Kir7.1 opening and relative cell hyperpolarization on the orexigenic arm. As seen during fasting, a decreased firing frequency would result from this condition.
Figure 6.
Figure 6.
Regulation of the melanocortin type 4 receptor (MC4R)-inwardly rectifying K+ (Kir)7.1 coupling complex by agouti-related peptide (AgRP) and α-melanocyte-stimulating hormones (α-MSH). AgRP induces channel openings by binding to MC4R and promoting a discrete “active” state that promotes Kir7.1 channel opening. The result at the PVHMC4R neuronal level is hyperpolarization and reduced firing frequency (Fig. 5). Conversely, α-MSH (or other MC4R Gαs-promoting agonists) induces channel closure, paraventricular nucleus (PVH)MC4R depolarization, increased firing frequency, and reduced food intake.
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References

    1. Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280: 69–77, 1998. doi:10.1126/science.280.5360.69. - DOI - PubMed
    1. Shaya D, Findeisen F, Abderemane-Ali F, Arrigoni C, Wong S, Nurva SR, Loussouarn G, Minor DL Jr.. Structure of a prokaryotic sodium channel pore reveals essential gating elements and an outer ion binding site common to eukaryotic channels. J Mol Biol 426: 467–483, 2014. doi:10.1016/j.jmb.2013.10.010. - DOI - PMC - PubMed
    1. Lenaeus MJ, Gamal El-Din TM, Ing C, Ramanadane K, Pomes R, Zheng N, Catterall WA. Structures of closed and open states of a voltage-gated sodium channel. Proc Natl Acad Sci USA 114: E3051–E3060, 2017. doi:10.1073/pnas.1700761114. - DOI - PMC - PubMed
    1. Wu J, Yan Z, Li Z, Qian X, Lu S, Dong M, Zhou Q, Yan N. Structure of the voltage-gated calcium channel Ca(v)1.1 at 3.6 A resolution. Nature 537: 191–196, 2016. doi:10.1038/nature19321. - DOI - PubMed
    1. Wu J, Yan Z, Li Z, Yan C, Lu S, Dong M, Yan N. Structure of the voltage-gated calcium channel Cav1.1 complex. Science 350: aad2395, 2015. doi:10.1126/science.aad2395. - DOI - PubMed

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