Pharmacological modulation and differential regulation of the cardiac gap junction proteins connexin 43 and connexin 40

Abstract

Gap junction channels provide the basis for the electrical syncytial properties of the heart as a communicating electrical network. Cardiac gap junction channels are predominantly composed of connexin 40 or connexin 43. The conductance of these channels (g(j)) can be regulated pharmacologically: substances which activate protein kinase C, protein kinase A or protein kinase G may alter Cx43 gap junction conductance. However, for PKC, this seems to be subtype specific. Thus, antiarrhythmic peptides can enhance g(j) via activation of PKCepsilon, while FGF-2 reduces g(j) via PKCepsilon. Lipophilic drugs can uncouple the channels. Besides an acute regulation of g(j), the expression of the cardiac connexins can also be regulated. A decrease in Cx43 with a concomitant increase in Cx40 has been found in end-stage failing hearts, while in renovascular hypertension, an increase in Cx43 has been described. Mediators like endothelin-1, angiotensin-II, TGF-beta, VEGF, and cAMP have been shown to increase Cx43. Interestingly, endothelin-1 and angiotensin-II increased Cx43 but did not affect Cx40 expression. In contrast, in humans suffering from atrial fibrillation (AF), the content in Cx40 can be enhanced while Cx43 was unaltered, although in several other studies, other changes of the cardiac connexins were found, which might be related to the type of AF. Regarding the role of calcium, the content in both Cx40 and Cx43 was decreased in cultured neonatal rat cardiomyocytes after 24 h administration of 100 nM verapamil. Thus, gap junctional channels can be affected pharmacologically either acutely by modulating gap junction conductance or chronically by altering gap junction protein expression. Interestingly, it appears that the expression of Cx43 and Cx40 can be differentially regulated.

Regulation of gap junction coupling in bovine ciliary epithelium

“…Although Cx43 might also be directly phosphorylated by PKA, most evidence argues against this view (20,35). Furthermore, in contrast to the current observations, cAMP commonly increases Cx43 gap junctional permeability in other preparations (20,35,51), albeit reducing message for Cx43 in rat Leydig cells (53). In addition, intracellular cAMP had no acute effect on Cx43 and Cx40 gap junctions expressed in HeLa cells (33).…”

“…Cx43 is known to be phosphorylated by protein kinase C, MAP kinase, and the pp60src kinase (35). Although Cx43 might also be directly phosphorylated by PKA, most evidence argues against this view (20,35). Furthermore, in contrast to the current observations, cAMP commonly increases Cx43 gap junctional permeability in other preparations (20,35,51), albeit reducing message for Cx43 in rat Leydig cells (53).…”

Alteration of Neuron-Glia Interactions in Neurodegeneration: Molecular Biomarkers and Therapeutic Strategy

“…Recently, novel protein interacting with Cx43 in astrocytes has been identified -brain-derived integrating factor-1 (BDIF-1) which is probably involved in regulating of astroglial activity (Ito et al, 2011). Pharmacological modulation of Cx43 can be achieved by various compounds (Dhein et al, 2002). T. Nakase et al (Nakase & Naus, 2004) reported that the activation of astrocytes associated with an increase in the expression and activity of connexin 43 protects neurons from ischemia-induced damage.…”

Strategies to invent cardiovascular drugs targeting cardiac gap junctions

“…Mediators like endothelin-1, angiotensin-II, TGFbeta, VEGF, and cAMP have been shown to increase Cx43 [4]. Pharmacologically changing endothelin-1, angiotensin-II, TGF-beta, VEGF, and cAMP et al into positive substances to mediate cardiac gap junction conductance for the treatment and prevention of cardiac diseases is also a good strategy.…”