KCNJ16 Membrane Protein Introduction

Introduction of KCNJ16

Inward rectifier potassium channel 16 (KCNJ16), also known as K_ir5.1, belongs to K_ir5 subfamily, inward-rectifier potassium channels (K_ir, IRK) family. Activated by phosphatidylinositol 4,5-bisphosphate (PIP2), the K_ir members play a wide range of roles in the establishment of resting membrane potential, inhibition of neurotransmitter responses, regulation of nitric oxide synthase, the decision of insulin release, etc. KCNJ16, which was mapped to chromosome 17q25, has a greater tendency to uptake potassium rather than spit out potassium. It has been well documented that KCNJ16 can form functional heterodimers with KCNJ10 which increase the potassium current, alter the responsiveness during hyperpolarizing pulses, and increase the unitary conductance of KCNJ10. Human KCNJ16 is predominantly expressed in kidney, pancreas and thyroid gland, especially in convoluted tubule cells of the kidney and in the acinar and ductal cells of the pancreas. Like other K_ir channels, KCNJ16 also possesses a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs).

Function of KCNJ16 Membrane Protein

The physiological roles of the KCNJ16 channel are performed by selective co-assembly with either KCNJ10 or KCNJ15 subunits to form novel heteromeric channels because KCNJ16 alone cannot produce functional K⁺ channels. The heteromeric KCNJ16/KCNJ10 are highly sensitive to inhibition by intracellular H⁺ (pHi) but insensitive to extracellular pH, providing a link between changes in intracellular pH and control of the resting membrane potential. So KCNJ16 is involved in the regulation of fluid and pH balance. Abundant co-expression in the brainstem, especially in several CO₂-chemosensitive nuclei, such as locus coeruleus (LC) neurons, KCNJ16/ KCNJ10 complex plays a crucial role in defining the pH sensitivity of LC neurons and may, therefore, affect their response to hypercapnic acidosis. In the kidney, KCNJ16/ KCNJ10 mediates basolateral K⁺ recycling in distal convoluted tubule (DCT), which is critical for Na⁺ reabsorption at the tubules. Disruption of Kcnj16 gene in mice induces a severe renal phenotype, including hypokalemic, hyperchloremic metabolic acidosis with hypercalciuria. As a pH-sensitive regulator of salt transport in DCT, KCNJ16 has great potentiality in genetic diagnosis of renal tubulopathies.

Fig.1 A cellular model for enhanced salt transport caused by deletion of Kcnj16. (Paulais, 2011)

Application of KCNJ16 Membrane Protein in Literature

1. Parrock S., et al. KCNJ10 mutations display differential sensitivity to heteromerisation with KCNJ16. Nephron Physiology. 2013, 123(3-4): 7-14. PubMed ID: 24193250
   
   

   In this review, the authors provide evidence that KCNJ10 mutations will display differential sensitivity to heteromerisation with KCNJ16. Co-expression with KCNJ10, KCNJ16 play widely roles in seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME)/epilepsy, ataxia, sensorineural deafness, and renal tubulopathy (EAST) syndrome.

2. Paulais M., et al. Renal phenotype in mice lacking the Kir5.1 (Kcnj16) K+ channel subunit contrasts with that observed in SeSAME/EAST syndrome. Proceedings of the National Academy of Sciences. 2011, 108(25): 10361-10366. PubMed ID: 21633011
   
   

   This article demonstrates that lacking the Kir5.1 (Kcnj16) K+ channel subunit in mice is the opposite of the phenotype seen in electrolyte imbalance (SeSAME)/epilepsy, ataxia, sensorineural deafness, and renal tubulopathy (EAST) syndrome, and they present hypokalemic, hyperchloremic metabolic acidosis with hypercalciuria.

3. Trapp S., et al. Respiratory responses to hypercapnia and hypoxia in mice with genetic ablation of Kir5.1 (Kcnj16). Experimental physiology. 2011, 96(4): 451-459. PubMed ID: 21239463
   
   

   The authors use Kir5.1 knockout mice (Kir5.1(-/-)) to study the role of KCNJ16 in the chemosensory control of breathing and they find that the transgenic mice present persistent metabolic acidosis and a clear respiratory phenotype.

4. Palygin O., et al. Essential role of Kir5.1 channels in renal salt handling and blood pressure control. JCI insight. 2017, 2(18). PubMed ID: 28931751
   
   

   This article reveals that KCNJ16 channels are key regulators of renal salt regulation in salt-sensitive hypertension. Kcnj16 knockout in Dahl salt-sensitive (SS) rats (SSKcnj16-/-) exhibit hypokalemia and reduced blood pressure.

5. Liu Y., et al. The human inward rectifier K+ channel subunit kir5.1 (KCNJ16) maps to chromosome 17q25 and is expressed in kidney and pancreas. Cytogenetic and Genome Research. 2000, 90(1-2): 60-63. PubMed ID: 11060447
   
   

   This article identifies the novel human Kir5.1 through database searches and demonstrates that Kir5.1 is mainly expressed in kidney, pancreas and thyroid gland.

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Reference

1. Paulais M, et al. (2011). Renal phenotype in mice lacking the Kir5.1 (Kcnj16) K+ channel subunit contrasts with that observed in SeSAME/EAST syndrome. Proceedings of the National Academy of Sciences. 108(25): 10361-10366.

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