Mechanism of PKCε Regulation of Cardiac GIRK Channel Gating

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2022 Dec 30

PMID 36584301

Authors

Kirin D Gada

Mengmeng Chang

Aishwarya Chandrashekar

Leigh D Plant

Sami F Noujaim

Diomedes E Logothetis

Affiliations

Soon will be listed here.

Abstract

G-protein-gated inwardly rectifying potassium (GIRK) channel activity is regulated by the membrane phospholipid, phosphatidylinositol-4,5-bisphosphate (PI 4,5P). Constitutive activity of cardiac GIRK channels in atrial myocytes, that is implicated in atrial fibrillation (AF), is mediated via a protein kinase C-ε (PKCε)-dependent mechanism. The novel PKC isoform, PKCε, is reported to enhance the activity of cardiac GIRK channels. Here, we report that PKCε stimulation leads to activation of GIRK channels in mouse atria and in human stem cell-derived atrial cardiomyocytes (iPSCs). We identified residue GIRK4(S418) which when mutated to Ala abolished, or to Glu, mimicked the effects of PKCε on GIRK currents. PKCε strengthened the interactions of the cardiac GIRK isoforms, GIRK4 and GIRK1/4 with PIP, an effect that was reversed in the GIRK4(S418A) mutant. This mechanistic insight into the PKCε-mediated increase in channel activity because of GIRK4(S418) phosphorylation, provides a precise druggable target to reverse AF-related pathologies due to GIRK overactivity.

Citing Articles

Angiotensin receptors and α-adrenergic receptors regulate native IK and phosphorylation-deficient GIRK4 (S418A) channels through different PKC isoforms.

Inderwiedenstrasse L, Kienitz M Pflugers Arch. 2024; 476(7):1041-1064.

PMID: 38658400 DOI: 10.1007/s00424-024-02966-5.

The W101C Mutation Induces Slower Pacing by Constitutively Active GIRK Channels in hiPSC-Derived Cardiomyocytes.

Kayser A, Dittmann S, Saric T, Mearini G, Verkerk A, Schulze-Bahr E Int J Mol Sci. 2023; 24(20).

PMID: 37894977 PMC: 10607318. DOI: 10.3390/ijms242015290.

PI(4,5)P2 regulates the gating of NaV1.4 channels.

Gada K, Kamuene J, Chandrashekar A, Kissell R, Yauch A, Plant L J Gen Physiol. 2023; 155(6).

PMID: 37043561 PMC: 10103707. DOI: 10.1085/jgp.202213255.

References

Andrade J, Khairy P, Dobrev D, Nattel S . The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res. 2014; 114(9):1453-68. DOI: 10.1161/CIRCRESAHA.114.303211. View

Lakatta E, Levy D . Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation. 2003; 107(2):346-54. DOI: 10.1161/01.cir.0000048893.62841.f7. View

Gazgalis D, Cantwell L, Xu Y, Thakur G, Cui M, Guarnieri F . Use of a Molecular Switch Probe to Activate or Inhibit GIRK1 Heteromers In Silico Reveals a Novel Gating Mechanism. Int J Mol Sci. 2022; 23(18). PMC: 9502415. DOI: 10.3390/ijms231810820. View

Takemoto Y, Slough D, Meinke G, Katnik C, Graziano Z, Chidipi B . Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule. FASEB J. 2017; 32(4):1778-1793. PMC: 5893172. DOI: 10.1096/fj.201700349R. View

Stanfield P . Homomers of Kir.3.4 in atrial myocytes: their relevance to atrial fibrillation. J Physiol. 2007; 585(Pt 1):1. PMC: 2375452. DOI: 10.1113/jphysiol.2007.145912. View

Nattel S, Carlsson L . Innovative approaches to anti-arrhythmic drug therapy. Nat Rev Drug Discov. 2006; 5(12):1034-49. DOI: 10.1038/nrd2112. View

Adney S, Ha J, Meng X, Kawano T, Logothetis D . A Critical Gating Switch at a Modulatory Site in Neuronal Kir3 Channels. J Neurosci. 2015; 35(42):14397-405. PMC: 4683693. DOI: 10.1523/JNEUROSCI.1415-15.2015. View

Lee S, Anderson A, Guzman P, Nakano A, Tolkacheva E, Wickman K . Atrial GIRK Channels Mediate the Effects of Vagus Nerve Stimulation on Heart Rate Dynamics and Arrhythmogenesis. Front Physiol. 2018; 9:943. PMC: 6060443. DOI: 10.3389/fphys.2018.00943. View

Idevall-Hagren O, Dickson E, Hille B, Toomre D, De Camilli P . Optogenetic control of phosphoinositide metabolism. Proc Natl Acad Sci U S A. 2012; 109(35):E2316-23. PMC: 3435206. DOI: 10.1073/pnas.1211305109. View

10.

Steinberg S . Structural basis of protein kinase C isoform function. Physiol Rev. 2008; 88(4):1341-78. PMC: 2899688. DOI: 10.1152/physrev.00034.2007. View

11.

Bettahi I, Marker C, Roman M, Wickman K . Contribution of the Kir3.1 subunit to the muscarinic-gated atrial potassium channel IKACh. J Biol Chem. 2002; 277(50):48282-8. DOI: 10.1074/jbc.M209599200. View

12.

Chan K, Langan M, Sui J, Kozak J, Pabon A, Ladias J . A recombinant inwardly rectifying potassium channel coupled to GTP-binding proteins. J Gen Physiol. 1996; 107(3):381-97. PMC: 2216996. DOI: 10.1085/jgp.107.3.381. View

13.

Kovoor P, Wickman K, Maguire C, Pu W, Gehrmann J, Berul C . Evaluation of the role of I(KACh) in atrial fibrillation using a mouse knockout model. J Am Coll Cardiol. 2001; 37(8):2136-43. DOI: 10.1016/s0735-1097(01)01304-3. View

14.

Palumbo E, Sweatt J, Chen S, Klann E . Oxidation-induced persistent activation of protein kinase C in hippocampal homogenates. Biochem Biophys Res Commun. 1992; 187(3):1439-45. DOI: 10.1016/0006-291x(92)90463-u. View

15.

Van Wagoner D, Nerbonne J . Molecular basis of electrical remodeling in atrial fibrillation. J Mol Cell Cardiol. 2000; 32(6):1101-17. DOI: 10.1006/jmcc.2000.1147. View

16.

Xue Y, Ren J, Gao X, Jin C, Wen L, Yao X . GPS 2.0, a tool to predict kinase-specific phosphorylation sites in hierarchy. Mol Cell Proteomics. 2008; 7(9):1598-608. PMC: 2528073. DOI: 10.1074/mcp.M700574-MCP200. View

17.

Voigt N, Friedrich A, Bock M, Wettwer E, Christ T, Knaut M . Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK,ACh channels in patients with chronic atrial fibrillation. Cardiovasc Res. 2007; 74(3):426-37. DOI: 10.1016/j.cardiores.2007.02.009. View

18.

Luchian T, Dascal N, Dessauer C, Platzer D, Davidson N, Lester H . A C-terminal peptide of the GIRK1 subunit directly blocks the G protein-activated K+ channel (GIRK) expressed in Xenopus oocytes. J Physiol. 1997; 505 ( Pt 1):13-22. PMC: 1160090. DOI: 10.1111/j.1469-7793.1997.013bc.x. View

19.

Keselman I, Fribourg M, Felsenfeld D, Logothetis D . Mechanism of PLC-mediated Kir3 current inhibition. Channels (Austin). 2008; 1(2):113-23. DOI: 10.4161/chan.4321. View

20.

Gada K, Kawano T, Plant L, Logothetis D . An optogenetic tool to recruit individual PKC isozymes to the cell surface and promote specific phosphorylation of membrane proteins. J Biol Chem. 2022; 298(5):101893. PMC: 9062429. DOI: 10.1016/j.jbc.2022.101893. View