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  • Cx has been shown to be serine phosphorylated


    Cx45 has been shown to be serine phosphorylated by CaMKII, CK1, PKA, and MAPK in HeLa muscarinic receptor antagonists [77], [78]. Phosphorylation by PKA and MAPK were associated with decreased junctional conductance [78], suggesting that phosphorylation of Cx45 may influence conduction properties. Overall, the roles of both Cx40 and Cx45 phosphorylation in gap junctional communication, particularly in myocardium, merits further research.
    Phosphatases and dephosphorylation of Cx43 Phosphorylation state of gap junctions is critical in regulating gap junction coupling between adjacent myocytes. Although phosphorylation occurs by protein kinase activity, the phosphorylation status of Cx43 is counteracted by protein phosphatases (Fig. 1). Since Cx43 phosphorylation sites are mostly serine sites at the C-terminus, dephosphorylation of Cx43 occurs mainly via serine/threonine protein phosphatases (PPs), particularly PP1 and PP2A in cardiac tissue [28], [29], [49]. Increased PP activity has been associated with CVDs, including HF, and atrial and ventricular arrhythmias [8], [26], [27], [42], [43]. We demonstrated that both PP1 and PP2A colocalize with Cx43 in cardiac tissue, and that the level of PP2A colocalized with Cx43 increased 2.5-fold in HF compared to controls, while the level of PP1 in HF remained the same [8]. This increased PP2A activity at the level of Cx43 in HF was associated with slow conduction and reduced intercellular coupling by slower LY dye transfer [8], [42], [43]. Non-phosphorylatable Cx43 gap junctions in S3A knock-in mice showed slow conduction and increased ventricular arrhythmias, while phosphatase-resistant Cx43 gap junctions in S3E knock-in mice were resistant to conduction slowing and less susceptible to arrhythmogenesis [12]. Thus, the mechanisms underlying protein phosphatase regulation of connexins are worth further investigation.
    Phosphatase regulation
    Introduction Gap junctions (GJs) are intercellular channels composed of two properly docked connexons (also known as hemichannels), allowing direct exchange of ions and small molecules to synchronize cells/tissues electrically and metabolically. Each connexon (hemichannel) is a hexamer of transmembrane proteins named connexins. In the human genome there are 21 genes encoding different connexins [1,2]. All connexins show similar topological structures with four transmembrane domains linked by two extracellular loops and one cytoplasmic loop with cytosolic amino terminus and carboxyl terminus. Different tissue cells commonly express different connexins. In the human heart, three connexins, Cx40, Cx43, and Cx45, are abundantly expressed in different regions of the myocardium [[3], [4], [5]]. Cx45 is the main connexin in the sinoatrial (SA) and atrioventricular (AV) nodal cells and is also expressed at a lower level in the atria and ventricles [3,6]. Both Cx40 and Cx43 are expressed in the atrial myocytes and Cx43 is the main connexin type in the ventricles [4]. In the ventricular conduction system all three connexins are expressed [3,4,7]. This regional specific expression pattern of connexins in the heart predicts a variety of cardiac gap junctions being formed. These gap junctions are critical for rapid propagation of action potentials in different regions of the heart leading to a highly synchronized rhythmic beating. It is well known that cardiac action potentials conduct at different velocity in different regions of the heart with the slowest propagation speed observed at the nodal regions [8,9], including AV node to cause an AV delay, which is important for effective sequential contractions of the atria and ventricles [8,10]. Many factors including sodium channels, calcium channels, potassium channels, cell geometry, passage length, and abundance and function of gap junction channels could contribute to the regional differences in conduction velocity [8,10]. Focusing on gap junctions, the GJ function can be quantitatively measured by coupling conductance (Gj). The Gj level could depend on the abundance and GJ type expressed in the cardiomyocytes. In addition, GJs in the heart could be dynamically modulated by a variety of physiological/pathological factors, including changes in intracellular ion concentrations (including protons/pH and divalent cations), chemicals, and transjunctional voltage (Vj). Transjunctional voltage-dependent gating (also known as Vj-gating) is a ubiquitous property for all GJs. Among the three cardiac connexins, Cx45 and Cx40 GJs have been shown to have prominent Vj-gating with rapid deactivation kinetics [[11], [12], [13], [14], [15], [16], [17]]. Vj-gating of Cx45 (or Cx40) GJs could reduce Gj to a much lower level (over 80% of original Gj) during large sustained Vjs [13,[15], [16], [17], [18]]. Previous functional characterizations of Vj-gating of GJs were carried out at room temperatures (20–25 °C). The effects of higher temperature near human body temperature on the Vj-gating of these connexins have not been studied, leaving an important knowledge gap. Previous studies demonstrated that the Gj could be dynamically regulated when sufficient junctional delay and repeating frequency (heart rate) provided [19] or during a simulated cardiac action potential protocol at the junction [[20], [21], [22]]. Here we investigated the extent of Vj-gating, the deactivation kinetics, and the recovery kinetics from deactivation of Cx45 and Cx40 GJs. Our results showed that temperature-dependent modulations were GJ (or connexin)-specific. The GJs muscarinic receptor antagonists most vulnerable to dynamic uncoupling was Cx45 GJs with retained dynamic uncoupling during the elevated temperatures tested. This unique dynamic uncoupling of Cx45 GJs might play a role in the delay of action potential propagation in the nodal cells of the heart.