Replacement of Connexin40 by Connexin45 in the Mouse

Abstract

Abstract-Gap junction channels, required for the propagation of cardiac impulse, are intercellular structures composed of connexins (Cx). Cx43, Cx40, and Cx45 are synthesized in the cardiomyocytes, and each of them has a unique cardiac expression pattern. Cx40 knock-in Cx45 mice were generated to explore the ability of Cx45 to replace Cx40, and to assess the functional equivalence of these two Cxs that are both expressed in the conduction system. ECGs revealed that the consequences resulting from the biallelic replacement of Cx40 by Cx45 were an increased duration of the P wave, and a prolonged and fractionated QRS complex. Epicardial mapping indicated that the conduction velocities (CV) in the right atrium and the ventricular myocardium, as well as conduction through the AV node, were unaffected. The significant reduction of the CV in the left atrium would be the most likely cause of the P-wave lengthening. In the right ventricle, a changed and prolonged activation in sinus rhythm was found in homozygous mutant mice, which may explain the prolongation and splitting of the QRS complex. Electrical mapping of the His bundle branches revealed that this was due to slow conduction measured in the right branch. The CV in the left branch was unchanged. Therefore, in the absence of Cx40, the upregulation of Cx45 in the heart results in a normal impulse propagation in the right atrium, the AV node, and the left His bundle branch only. (Circ Res. 2004;94:100-109.)

Mouse Model of SCN5A -Linked Hereditary Lenègre’s Disease

“…25 Moreover, conduction velocity in the His bundle branches of the mouse is not faster than in the working myocardium. 12 Another major difference between mouse and human is that the mouse heart contracts 10 times more often per time unit than the human heart. Different cardiac sizes lead to different constraints.…”

“…10,12 For the experiments comparing young (14 to 16 weeks old) and old (50 to 73 weeks old) mice, total cellular protein was isolated from 5 hearts (total ventricular section) in each group (young versus old and WT versus Scn5a ϩ/Ϫ ) as described previously. 10 Protein content of the supernatant was assessed according to Lowry's method.…”

“…Moorman, Academic Medical Center, Amsterdam, the Netherlands) and desmin (Sigma Aldrich); rabbit polyclonal antibodies against Cx43 or connexin40 (Cx40), 12 N-cadherin (Sigma Aldrich), and skeletal ␣-actin (␣-SKA, kindly provided by Dr S. Clement, University of Geneva, Switzerland). Secondary antibodies (Texas Red-and FITC-conjugated whole IgG) were purchased from Jackson Laboratories.…”

The hidden secrets of the hibernator’s heart may protect against arrhythmias

“…However, even at normothermia, the relation between gap junction density and conduction velocity is not well established and is far from linear, 10 let alone at low temperature, as we pointed out previously. 11 A substitution of Cx43 by Cx45 seems to decrease rather than increase conduction velocity, at least at normothermia, 12 but addition of Cx45 to increased levels of Cx43 as demonstrated in this study 1 may help support conduction at low temperature.…”

Sudden cardiac death in the young: cytokines and pathways

“…Cx43 conditional knockout mice with induced deletion of Cx43 in the heart exhibited reduced conduction velocity, increased dispersion of conduction, and enhanced electrical vulnerability on the ventricular level (32). Experimental studies revealed that Cx45 could be a substitute of Cx40 when the latter was deficient in the atrioventricular node, at least partly identifying the compensating properties of various Cx proteins (33). In 156 probands with progressive familial heart block type I, a novel germ line heterozygous missense mutation in exon 2 of the Cx40 gene GJA5 was identified, whereas mutations were not found in connexin genes GJA1 (Cx43) or GJC1 (Cx45).…”