GIRK3 deletion facilitates kappa opioid signaling in chondrocytes, delays vascularization and promotes bone lengthening in mice
“Activation of G protein-coupled receptor (GPCR) signaling pathways is crucial for skeletal development and long bone growth. protein-gated inwardly-rectifying K+ (GIRK) channel genes are key functional components and effectors of GPCR signaling pathways in excitable cells of the heart and brain, but their roles in non-excitable cells that directly contribute to endochondral bone formation have not been studied. In this study, we analyzed skeletal phenotypes of Girk2−/−, Girk3−/− and Girk2/3−/− mice. Bones from 12-week-old Girk2−/− mice were normal in length, but femurs and tibiae from Girk3−/− and Girk2/3−/− mice were longer than age-matched controls at 12-weeks-old. Epiphyseal chondrocytes from 5-day-old Girk3−/− mice expressed higher levels of genes involved in collagen chain trimerization and collagen fibril assembly, lower levels of genes encoding VEGF receptors, and produced larger micromasses than wildtype chondrocytes in vitro. Girk3−/− chondrocytes were also more responsive to the kappa opioid receptor (KOR) ligand dynorphin, as evidenced by greater pCREB expression, greater cAMP and GAG production, and upregulation of Col2a1 and Sox9 transcripts. Imaging studies showed that Kdr (Vegfr2) and endomucin expression was dramatically reduced in bones from young Girk3−/− mice, supporting a role for delayed vasculogenesis and extended postnatal endochondral bone growth. Together these data indicate that GIRK3 controls several processes involved in bone lengthening.”
“GIRK channels are homo- and hetero-tetramers formed by four mammalian GIRK subunits (GIRK1/Kcnj3, GIRK2/Kcnj6, GIRK3/Kcnj9, and GIRK4/Kcnj5). GIRK channels are activated when GPCR ligands stimulate pertussis toxin-sensitive Gi/o-G proteins; the liberated Gβγ subunit then binds to GIRK channels and increases their gating. The resultant efflux of K+ reduces the excitability of neuronsand cardiomyocytes. Knockout studies in mice have shown that GIRK2-containing GIRK channels mediate pain relief evoked by opioids and other analgesics. In chondrocytes, K+ efflux reduces swelling during unloading and can affect proteoglycan secretion”<-so maybe GIRK2 and GIRK3 knockouts have more chondrocyte hypertrophy and are more responsive to mechanical loading.
“GIRK2 mutations in patients with Keppen Lubinsky syndrome, which is characterized by growth above the 50th to 75th percentile at birth with subsequent developmental delays and other phenotypes “
“Girk3 deletion increases femur and tibia lengths and augments kappa opioid signaling in chondrocytes. Thus, these data identify GIRK3 as a suppressor of bone lengthening and kappa opioid activity in developing skeletons.”
“Numerous GPCR-signaling pathways, including kappa opioids, influence growth.”
Need to get the full paper and research more on GIRK3.