Kcnj5 Knockout mouse models

Kcnj5, the mouse ortholog of human KCNJ5, encodes GIRK4 (Kir3.4), the G protein-gated inward rectifier subunit that partners with GIRK1 to carry the atrial acetylcholine-activated current IKACh downstream of M2 muscarinic receptors, and that also forms channels in adrenal zona glomerulosa, pancreatic islets, and restricted brain regions. Channel opening requires direct Gbeta gamma binding together with PIP2, and GIRK4 uniquely can form functional homotetramers, unlike GIRK1. The dominant disease logic is gain of function: somatic and germline KCNJ5 mutations at Gly151 and Leu168 disrupt the selectivity filter, admit sodium, and depolarize glomerulosa cells, driving aldosterone-producing adenomas and familial hyperaldosteronism type 3. Selectivity-filter knockins therefore model primary aldosteronism directly, while conditional nulls address vagal heart rate control and adrenal potassium handling separately. GIRK1, GIRK2, and GIRK3 encoded by Kcnj3, Kcnj6, and Kcnj9 assemble in overlapping combinations, so define subunit composition electrophysiologically before assigning a phenotype to this locus.

Whole body loss of Kcnj5 gives the clearest readout when the question is whether the gene is required at all. Follow up tissue work can still move to a conditional allele if lethality or compensation appears.