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KCNJ5 Membrane Protein Introduction

Introduction of KCNJ5

G protein-activated inward rectifier potassium channel 4 (GIRK4, also called KCNJ5 or Kir3.4) is a type of G protein-gated ion channel and is encoded by the KCNJ5 gene. Kir3.4 is one of four identified Kir3 channels, which can form homo-tetramers or hetero-tetramers (more commonly) with Kir3.1 (KCNJ3), Kir3.2 (KCNJ6) or Kir3.3 (KCNJ9) and the assemblies of Kir3 subunits is various among different tissues and cell types in every channel, corresponding to their diverse functional roles. Similar to other members of the Kir family, KCNJ5 also contains two transmembrane segments (M1 and M2) with a pore loop in between, and cytoplasmic N- and C-terminal domains. Conducting K+ currents more in the inward direction than outward, KCNJ5 plays an important role in setting the resting membrane potential. Gene KCNJ5 was mapped to chromosome 11q24, and there are two transcript variants have been found.

Basic Information of KCNJ5
Protein Name G protein-activated inward rectifier potassium channel 4
Gene Name KCNJ5
Aliases Kir3.4
Organism Homo sapiens (Human)
UniProt ID P48544
Transmembrane Times 2
Length (aa) 419
Sequence MAGDSRNAMNQDMEIGVTPWDPKKIPKQARDYVPIATDRTRLLAEGKKPRQRYMEKSGKCNVHHGNVQETYRYLSDLFTTLVDLKWRFNLLVFTMVYTVTWLFFGFIWWLIAYIRGDLDHVGDQEWIPCVENLSGFVSAFLFSIETETTIGYGFRVITEKCPEGIILLLVQAILGSIVNAFMVGCMFVKISQPKKRAETLMFSNNAVISMRDEKLCLMFRVGDLRNSHIVEASIRAKLIKSRQTKEGEFIPLNQTDINVGFDTGDDRLFLVSPLIISHEINQKSPFWEMSQAQLHQEEFEVVVILEGMVEATGMTCQARSSYMDTEVLWGHRFTPVLTLEKGFYEVDYNTFHDTYETNTPSCCAKELAEMKREGRLLQYLPSPPLLGGCAEAGLDAEAEQNEEDEPKGLGGSREARGSV

Function of KCNJ5 Membrane Protein

Deep researches of KCNJ5 (forming a K-selective channel by heterotetramerizing with KCNJ3) in the atria where it is involved in mediating the cholinergic effects of the vagus nerve on the heart have been performed in last decades. Notably, it is reported that the channel KCNJ5 is significantly expressed in adrenal cortex and only subsequently confirmed on the zona glomerulosa cell membrane and transports potassium out of the cell. It is documented that KCNJ5 mutations are closely associated with both the sporadic and the familial forms of primary hyperaldosteronism. For example, KCNJ5 mutation (T158A) may change the selectivity filter of the channel, resulting in loss of ion selectivity and sodium entry, thus leading to membrane depolarization (in pathological). However, adrenal zona glomerulosa cells display high resting K+ conductance, responsible for cell membrane hyperpolarization (in physiological). In the past few years, a flurry of KCNJ5 mutations (G151R, L168R G151E, Y152C, I157S, insT149, etc.) localized in or near the KCNJ5 selectivity filter have been described, leading to elevated expression of aldosterone synthase and aldosterone production in hyperaldosteronism type III.

The association of mutant KCNJ5 with aldosterone-producing adenoma and Mendelian aldosteronism. Fig.1 The association of mutant KCNJ5 with aldosterone-producing adenoma and Mendelian aldosteronism. (Choi, 2011)

Application of KCNJ5 Membrane Protein in Literature

  1. Gomez L., et al. Association of the KCNJ5 gene with Tourette Syndrome and Attention-Deficit/Hyperactivity Disorder. Genes. Brain and Behavior. 2014, 13(6): 535-542. PubMed ID: 24840790

    In this article, the authors revealed that KCNJ5 was associated with Tourette Syndrome (TS) and Attention-Deficit/Hyperactivity Disorder (ADHD) after studies of massive samples from 170 nuclear families with TS, however, the functional variant(s) remained to be identified.

  2. Kuppusamy M., et al. A novel KCNJ5-insT149 somatic mutation close to, but outside, the selectivity filter causes resistant hypertension by loss of selectivity for potassium. The Journal of Clinical Endocrinology & Metabolism. 2014, 99(9): E1765-E1773. PubMed ID: 25057880

    This article reported that the mutated KCNJ5-insT149 channel exhibited pathological Na+ permeability, membrane depolarization, raised cytosolic Ca2+, as well as increased production of aldosterone, causing resistant hypertension.

  3. Velarde-Miranda C., et al. Regulation of aldosterone biosynthesis by the Kir3.4 (KCNJ 5) potassium channel. Clinical and Experimental Pharmacology and Physiology. 2013, 40(12): 895-901. PubMed ID: 23829355

    This article verified that suppression of the transcription of KCNJ5 mediated the secretion of angiotensin II-stimulated aldosterone, resulting in membrane depolarization, mobilization of intracellular calcium, activation of the calcium-calmodulin pathway, and leading to increased aldosterone synthesis terminally.

  4. Hardege I., et al. Novel insertion mutation in KCNJ5 channel produces constitutive aldosterone release from H295R Cells. Molecular endocrinology. 2015, 29(10): 1522-1530. PubMed ID: 26340408

    The authors re-sequenced the KCNJ5 channel in a large Australian primary aldosteronism cohort and identified a novel mutation (A139_F142dup), which increased basal aldosterone release 2.3-fold compared with the wild type. And they confirmed the frequency of somatic KCNJ5 mutations in APAs.

  5. Monticone S., et al. A novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III. The Journal of Clinical Endocrinology & Metabolism. 2013, 98(11): E1861-E1865. PubMed ID: 24037882

    The authors described a new germline mutation (Y152C) in KCNJ5 responsible for Familial Hyperaldosteronism Type III, which caused pathological Na+ permeability, cell membrane depolarization, and disturbed intracellular Ca2+ homeostasis.

  6. Choi M., et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011, 331(6018): 768-772. PubMed ID: 1198785

    The authors identified two recurrent somatic mutations (G151R, L168R) in and near the selectivity filter of the potassium (K+) channel KCNJ5 in a Mendelian form of severe aldosteronism and massive bilateral adrenal hyperplasia.

KCNJ5 Preparation Options

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Reference

  1. Choi M, et al. (2011). K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 331(6018): 768-772.

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