Pharmacological modulation and differential regulation of the cardiac gap junction proteins connexin 43 and connexin 40.
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.
Dhein
Stefan
S
Clinic for Cardiac Surgery, Heart Center Leipzig, University of Leipzig, Struempellstr. 39, 04289, Leipzig, Germany. dhes@medizin.uni-leipzig.de
Polontchouk
Lioudmila
L
Salameh
Aida
A
Haefliger
Jaques Antoine
JA
D000818:Animals; D018031:Connexin 43 / Q000096:biosynthesis / Q000187:drug effects* / Q000502:physiology; D017630:Connexins / Q000096:biosynthesis / Q000187:drug effects* / Q000502:physiology; D004553:Electric Conductivity; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000097003:Gap Junction alpha-5 Protein
D018031:Connexin 43; D017630:Connexins; D000097003:Gap Junction alpha-5 Protein