# KCNJ5

## Overview
The KCNJ5 gene encodes the potassium inwardly rectifying channel subfamily J member 5 (Kir3.4), a critical component of the G-protein-activated inwardly rectifying potassium (GIRK) channels. These channels are integral membrane proteins that play a vital role in maintaining the resting membrane potential and regulating cellular excitability by facilitating the inward flow of potassium ions. Kir3.4 is predominantly expressed in the adrenal gland and heart, where it contributes to aldosterone production and cardiac electrophysiology, respectively. The protein forms part of a tetrameric channel complex, which can be composed of either homotetramers or heterotetramers with other GIRK subunits. Mutations in KCNJ5 have been linked to various clinical conditions, including aldosterone-producing adenomas and cardiac arrhythmias, underscoring its significance in both endocrine and cardiovascular health (Meyer2023Relevance; Hibino2010Inwardly; Mulatero2012Role).

## Structure
The KCNJ5 gene encodes the Kir3.4 protein, a subunit of the G-protein-activated inwardly rectifying potassium (GIRK) channels. The Kir3.4 protein is part of a tetrameric complex that can form either homotetramers or heterotetramers with other subunits like Kir3.1 (KCNJ3) (Meyer2023Relevance; Mulatero2012Role). Each subunit of the channel contains two transmembrane alpha-helices and a pore-forming loop, which is crucial for ion selectivity (Meyer2023Relevance). The pore domain includes a conserved Gly-Tyr-Gly sequence, typical of K+ selective channels (Mulatero2012Role).

The protein's structure is further characterized by intracellular N-terminal and C-terminal regions. The C-terminal region is essential for the channel's localization to the cell surface, while specific amino acids in this region are necessary for the formation of functional heterotetramers (Meyer2023Relevance). Structural modeling has shown that mutations in the selectivity filter, such as I157S, can disrupt the channel's ion selectivity by causing conformational changes (Charmandari2012A). These structural features are critical for the channel's role in maintaining membrane potential and ion homeostasis in various tissues, including the heart and adrenal gland (Meyer2023Relevance).

## Function
The KCNJ5 gene encodes a protein that is part of the G protein-sensitive inwardly rectifying potassium channels, specifically known as Kir3.4 or GIRK4. These channels are crucial for maintaining the resting membrane potential and regulating cellular excitability by allowing potassium ions to flow more easily into the cell than out. In healthy human cells, KCNJ5 is primarily expressed in the adrenal gland, particularly in the zona glomerulosa of the adrenal cortex, where it plays a significant role in aldosterone production. This process is mediated through the activation of voltage-gated Ca2+ channels following increased sodium conductance and cell depolarization due to KCNJ5 activity (Nishikido2020Regulation).

In the heart, KCNJ5 forms part of the G-protein-activated inwardly rectifying potassium channel complex, which is involved in cardiac electrophysiology. These channels contribute to heart rate variability by mediating parasympathetic effects through the muscarinergic M2-receptor, influencing cardiac rhythm and action potential duration (Hibino2010Inwardly; Binas2019miR221). The protein's activity is regulated by interactions with G protein subunits, which facilitate rapid channel activation in response to physiological stimuli (Hibino2010Inwardly).

## Clinical Significance
Mutations in the KCNJ5 gene are significantly associated with aldosterone-producing adenomas (APAs) and primary aldosteronism, a condition characterized by excessive aldosterone production leading to hypertension. These mutations, such as G151R, L168R, and T158A, alter the selectivity filter of the potassium channel, increasing sodium conductance and causing cellular depolarization. This results in the activation of voltage-gated calcium channels, promoting aldosterone secretion and cell proliferation, which contribute to the development of APAs (Scholl2013New; Tauber2014Pharmacology; Hattangady2016Mutated).

KCNJ5 mutations are more prevalent in women and are linked to higher plasma aldosterone levels, although they do not affect adenoma size or surgical outcomes (Scholl2013New). In familial hyperaldosteronism type III (FH-III), specific KCNJ5 mutations, such as T158A, lead to severe hypertension and hypokalemia, often requiring surgical intervention (Mulatero2012Role).

Beyond endocrine disorders, KCNJ5 variants have been implicated in cardiac pathologies, including atrial fibrillation and sinus node dysfunction. These conditions arise from disrupted channel activation and altered sinoatrial node pacemaker activity, highlighting the gene's role in both endocrine and cardiac health (Meyer2023Relevance).

## Interactions
KCNJ5, encoding the GIRK4 protein, is involved in various protein interactions that are crucial for its function in cellular excitability and signal transduction. GIRK4 forms part of the G-protein-activated inwardly rectifying potassium (GIRK) channels, which are essential for modulating cardiac electrical activity. These channels interact with G-protein subunits, particularly Gβγ, to facilitate channel activation. Mutations in KCNJ5, such as R52H and E246K, impair the interaction with Gβγ, leading to non-functional channels (Shalomov2022A).

KCNJ5 also participates in multiprotein complexes, influencing cardiac electrophysiology. The protein interacts with other ion channels and regulatory proteins, which are significant for maintaining proper channel expression and function. In cardiac tissue, KCNJ5 has been identified to have 45 protein interactors, highlighting its role in complex protein networks that regulate cardiac function (Maurya2023Outlining).

Additionally, KCNJ5 is a target of miR-208b, a microRNA that binds to its 3'-UTR, affecting its expression. This interaction has functional implications for ion current regulation in cardiomyocytes, as demonstrated by reduced carbachol-induced thallium current in cells transfected with miR-208b mimics (Hupfeld2021miR208b).


## References


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[12. (Binas2019miR221) Stephanie Binas, Maria Knyrim, Julia Hupfeld, Udo Kloeckner, Sindy Rabe, Sigrid Mildenberger, Katja Quarch, Nicole Strätz, Danny Misiak, Michael Gekle, Claudia Grossmann, and Barbara Schreier. Mir-221 and -222 target cacna1c and kcnj5 leading to altered cardiac ion channel expression and current density. Cellular and Molecular Life Sciences, 77(5):903–918, July 2019. URL: http://dx.doi.org/10.1007/s00018-019-03217-y, doi:10.1007/s00018-019-03217-y. This article has 21 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00018-019-03217-y)