Key result
IP3R physically interacts with Cx43 and participates in the regulation of Cx43 phosphorylation on S279/282, thereby affecting gap junction intercellular communication in ventricular myocytes.
IP3R physically interacts with Cx43 in ventricular myocytes and regulates gap junction intercellular communication via Cx43 phosphorylation at S279/282, providing a novel mechanism for cardiac electrical coupling.
No immediate clinical implications for arrhythmia care; leaves open IP3R as Cx43 regulator in ventricular myocardium.
Inositol 1,4,5-trisphosphate receptor (IP 3 R) plays a pivotal role in the Ca 2+ release process in a variety of cell types. Additionally, IP 3 R is distributed in ventricular intercalated discs, but its function(s) in this particular site remains unknown. Connexin (Cx43), the predominant gap junction (GJ) protein in ventricular myocardium, is linked to several signaling pathways that regulate Cx43 properties by (de)phosphorylation on multiple residues. Here, we investigated the regulatory role of IP 3 R in cell-cell communication and the mechanism(s) underlying this effect. In neonatal rat and adult mouse ventricular myocytes IP 3 R co-localized and co-immunoprecipitated with Cx43 in GJ plaques detected by immunostaining and western blot assays. Blocking IP 3 R with antagonists or silencing pan-IP 3 R expression with shRNA hindered the 6-carboxyfluorescein (6-CFDA) diffusion through GJs and desynchronized Ca 2+ transients among confluent neonatal myocytes in culture, whereas stimulation of IP 3 R with IP 3 ester or ATP exerted the opposite effect. Likewise, 6-CFDA propagation through GJs was modulated by IP 3 R activation or inhibition in cell pairs of isolated adult cardiomyocytes. Furthermore, IP 3 R activation or IP 3 R suppression promoted or suppressed, respectively, Cx43 phosphorylation on S279/282. Site-directed mutagenesis indicated that expression of a mutant Cx43-S282A (alanine) inhibited S279/282 phosphorylation and GJ permeability, while the S279A mutant showed the opposite effect in ventricular myocytes. Expression of these mutants in HEK293 cells revealed that cells with a dual S279/282 mutation failed to express exogenous Cx43, whereas cells with a single S279 or S282 mutation displayed Cx43 overexpression with increased phosphorylation of S279/282 and promotion of intercellular communication. These results demonstrated, for the first time, that IP 3 R physically interacts with Cx43 and participates in the regulation of Cx43 phosphorylation on S279/282, thereby affecting GJ intercellular communication in ventricular myocytes.
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Kang et al. (2014) studied this question. IP3R activation or inhibition vs. Control (vehicle or scramble shRNA) was evaluated on Gap junction intercellular communication and Cx43 phosphorylation on S279/282. IP3R physically interacts with Cx43 and participates in the regulation of Cx43 phosphorylation on S279/282, thereby affecting gap junction intercellular communication in ventricular myocytes.
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