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Extracellular sodium and potassium levels modulate cardiac conduction in mice heterozygous null for the Connexin43 gene.

ABSTRACT: Several studies have disagreed on measurements of cardiac conduction velocity (CV) in mice with a heterozygous knockout of the connexin gene Gja1--a mutation that reduces the gap junction (GJ) protein, Connexin43 (Cx43), by 50 %. We noted that perfusate ionic composition varied between studies and hypothesized that extracellular ionic concentration modulates CV dependence on GJs. CV was measured by optically mapping wild-type (WT) and heterozygous null (HZ) hearts serially perfused with solutions previously associated with no change (Solution 1) or CV slowing (Solution 2). In WT hearts, CV was similar for Solutions 1 and 2. However, consistent with the hypothesis, Solution 2 in HZ hearts slowed transverse CV (CVT) relative to Solution 1. Previously, we showed CV slowing in a manner consistent with ephaptic conduction correlated with increased perinexal inter-membrane width (W P) at GJ edges. Thus, W P was measured following perfusion with systematically adjusted [Na(+)]o and [K(+)]o in Solutions 1 and 2. A wider W P was associated with reduced CVT in WT and HZ hearts, with the greatest effect in HZ hearts. Increasing [Na(+)]o increased CVT only in HZ hearts. Increasing [K(+)]o slowed CVT in both WT and HZ hearts with large W P but only in HZ hearts with narrow W P.When perinexi are wide, decreasing excitability by modulating [Na(+)]o and [K(+)]o increases CV sensitivity to reduced Cx43. By contrast, CV is less sensitive to Cx43 and ion composition when perinexi are narrow. These results are consistent with cardiac conduction dependence on both GJ and non-GJ (ephaptic) mechanisms.

SUBMITTER: George SA

PROVIDER: S-EPMC5131712 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Extracellular sodium and potassium levels modulate cardiac conduction in mice heterozygous null for the Connexin43 gene.

George Sharon A SA Sciuto Katherine J KJ Lin Joyce J Salama Mohamed E ME Keener James P JP Gourdie Robert G RG Poelzing Steven S

Pflugers Archiv : European journal of physiology 20150314 11

<h4>Unlabelled</h4>Several studies have disagreed on measurements of cardiac conduction velocity (CV) in mice with a heterozygous knockout of the connexin gene Gja1--a mutation that reduces the gap junction (GJ) protein, Connexin43 (Cx43), by 50 %. We noted that perfusate ionic composition varied between studies and hypothesized that extracellular ionic concentration modulates CV dependence on GJs. CV was measured by optically mapping wild-type (WT) and heterozygous null (HZ) hearts serially per ...[more]

PMID: 25771952

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Project description:The Alzheimer BACE1 enzyme cleaves numerous substrates, with largely unknown physiological consequences. We have previously identified the contribution of elevated BACE1 activity to voltage-gated sodium channel Na(v)1.1 density and neuronal function. Here, we analyzed physiological changes in sodium channel metabolism in BACE1-null mice. Mechanistically, we first confirmed that endogenous BACE1 requires its substrate, the ?-subunit Na(v)?(2), to regulate levels of the pore-forming ?-subunit Na(v)1.1 in cultured primary neurons. Next, we analyzed sodium channel ?-subunit levels in brains of BACE1-null mice at 1 and 3 months of age. At both ages, we found that Na(v)1.1 protein levels were significantly decreased in BACE1-null versus wild-type mouse brains, remaining unchanged in BACE1-heterozygous mouse brains. Interestingly, levels of Na(v)1.2 and Na(v)1.6 ?-subunits also decreased in 1-month-old BACE1-null mice. In the hippocampus of BACE1-null mice, we found a robust 57% decrease of Na(v)1.1 levels. Next, we performed surface biotinylation studies in acutely dissociated hippocampal slices from BACE1-null mice. Hippocampal surface Na(v)1.1 levels were significantly decreased, but Na(v)1.2 surface levels were increased in BACE1-null mice perhaps as a compensatory mechanism for reduced surface Na(v)1.1. We also found that Na(v)?(2) processing and Na(v)1.1 mRNA levels were significantly decreased in brains of BACE1-null mice. This suggests a mechanism consistent with BACE1 activity regulating mRNA levels of the ?-subunit Na(v)1.1 via cleavage of cell-surface Na(v)?(2). Together, our data show that endogenous BACE1 activity regulates total and surface levels of voltage-gated sodium channels in mouse brains. Both decreased Na(v)1.1 and elevated surface Na(v)1.2 may result in a seizure phenotype. Our data caution that therapeutic BACE1 activity inhibition in Alzheimer disease patients may affect Na(v)1 metabolism and alter neuronal membrane excitability in Alzheimer disease patients.

Dataset Information

Extracellular sodium and potassium levels modulate cardiac conduction in mice heterozygous null for the Connexin43 gene.

Publications

Extracellular sodium and potassium levels modulate cardiac conduction in mice heterozygous null for the Connexin43 gene.

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