Author: Dissanayake, Lashodya V ; Geurts, Aron ; Levchenko, Vladislav ; Zietara, Adrian ; Staruschenko, Alexander ; Klemens, Christine A ; Denton, Jerod S ; Palygin, Oleg

High K⁺ supplementation is correlated with a lower risk of the composite of death, major cardiovascular events, and ameliorated blood pressure, but the exact mechanisms have not been established. Inwardly rectifying K⁺ (K_ir) channels expressed in the basolateral membrane of the distal nephron play an essential role in maintaining electrolyte homeostasis. Mutations in this channel family have been shown to result in strong disturbances in electrolyte homeostasis, among other symptoms. K_ir7.1 is a member of the ATP-regulated subfamily of K_ir channels. However, its role in renal ion transport and its effect on blood pressure have yet to be established. Our results indicate the localization of K_ir7.1 to the basolateral membrane of aldosterone-sensitive distal nephron cells. To examine the physiological implications of K_ir7.1, we generated a knockout of K_ir7.1 (Kcnj13) in Dahl salt-sensitive (SS) rats and deployed chronic infusion of a specific K_ir7.1 inhibitor, ML418, in the wild-type Dahl SS strain. Knockout of Kcnj13 (Kcnj13^-/-) resulted in embryonic lethality. Heterozygous Kcnj13^+/- rats revealed an increase in K⁺ excretion on a normal-salt diet but did not exhibit a difference in blood pressure development or plasma electrolytes after 3 wk of a high-salt diet. Wild-type Dahl SS rats exhibited increased renal K_ir7.1 expression when dietary K⁺ was increased. K⁺ supplementation also demonstrated that Kcnj13^+/- rats excreted more K⁺ on normal salt. The development of hypertension was not different when rats were challenged with high salt for 3 wk, although Kcnj13^+/- rats excrete less Na⁺. Interestingly, chronic infusion of ML418 significantly increased Na⁺ and Cl^- excretion after 14 days of high salt but did not alter salt-induced hypertension development. Here, we found that reduction of K_ir7.1 function, either through genetic ablation or pharmacological inhibition, can influence renal electrolyte excretion but not to a sufficient degree to impact the development of SS hypertension.NEW & NOTEWORTHY To investigate the role of the K_ir7.1 channel in salt-sensitive hypertension, its function was examined using complementary genetic and pharmacological approaches. The results revealed that although reducing K_ir7.1 expression had some impact on maintaining K⁺ and Na⁺ balance, it did not lead to a significant change in the development or magnitude of salt-induced hypertension. Hence, it is probable that K_ir7.1 works in conjunction with other basolateral K⁺ channels to fine-tune membrane potential.

01 Aug 2022·CNS Neuroscience & Therapeutics

SUMOylation of Kir7.1 participates in neuropathic pain through regulating its membrane expression in spinal cord neurons

Article

Author: Xin, Wen‐Jun ; Wang, Han ; Xu, Ting ; Lv, You‐You ; Guo, Rui‐Xian ; Fan, Hai‐Ting

AbstractAimsPotassium (K+) channels have been demonstrated to play a prominent involvement in nociceptive processing. Kir7.1, the newest members of the Kir channel family, has not been extensively studied in the CNS, and its function remains largely unknown. The present study investigated the role of spinal Kir7.1 in the development of pathological pain.Methods and ResultsNeuropathic pain was induced by spared nerve injury (SNI). The mechanical sensitivity was assessed by von Frey test. Immunofluorescence staining assay revealed that Kir7.1 was predominantly expressed in spinal neurons but not astrocytes or microglia in normal rats. Western blot results showed that SNI markedly decreased the total and membrane expression of Kir7.1 in the spinal dorsal horn accompanied by mechanical hypersensitivity. Blocking Kir7.1 with the specific antagonist ML418 or knockdown kir7.1 by siRNA led to mechanical allodynia. Co‐IP results showed that the spinal kir7.1 channels were decorated by SUMO‐1 but not SUMO‐2/3, and Kir7.1 SUMOylation was upregulated following SNI. Moreover, inhibited SUMOylation by GA (E1 inhibitor) or 2‐D08 (UBC9 inhibitor) can increase the spinal surface Kir7.1 expression.ConclusionSUMOylation of the Kir7.1 in the spinal cord might contribute to the development of SNI‐induced mechanical allodynia by decreasing the Kir7.1 surface expression in rats.

01 Sep 2017·Molecular PharmacologyQ3 · MEDICINE

Pore Polarity and Charge Determine Differential Block of Kir1.1 and Kir7.1 Potassium Channels by Small-Molecule Inhibitor VU590

Q3 · MEDICINE

Article

Author: Figueroa, Eric E ; Meiler, Jens ; Kharade, Sujay V ; Denton, Jerod S ; Sheehan, Jonathan H

VU590 was the first publicly disclosed, submicromolar-affinity (IC₅₀ = 0.2 μM), small-molecule inhibitor of the inward rectifier potassium (Kir) channel and diuretic target, Kir1.1. VU590 also inhibits Kir7.1 (IC₅₀ ∼ 8 μM), and has been used to reveal new roles for Kir7.1 in regulation of myometrial contractility and melanocortin signaling. Here, we employed molecular modeling, mutagenesis, and patch clamp electrophysiology to elucidate the molecular mechanisms underlying VU590 inhibition of Kir1.1 and Kir7.1. Block of both channels is voltage- and K⁺-dependent, suggesting the VU590 binding site is located within the pore. Mutagenesis analysis in Kir1.1 revealed that asparagine 171 (N171) is the only pore-lining residue required for high-affinity block, and that substituting negatively charged residues (N171D, N171E) at this position dramatically weakens block. In contrast, substituting a negatively charged residue at the equivalent position in Kir7.1 enhances block by VU590, suggesting the VU590 binding mode is different. Interestingly, mutations of threonine 153 (T153) in Kir7.1 that reduce constrained polarity at this site (T153C, T153V, T153S) make wild-type and binding-site mutants (E149Q, A150S) more sensitive to block by VU590. The Kir7.1-T153C mutation enhances block by the structurally unrelated inhibitor VU714 but not by a higher-affinity analog ML418, suggesting that the polar side chain of T153 creates a barrier to low-affinity ligands that interact with E149 and A150. Reverse mutations in Kir1.1 suggest that this mechanism is conserved in other Kir channels. This study reveals a previously unappreciated role of membrane pore polarity in determination of Kir channel inhibitor pharmacology.

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