The promiscuous nature of the cardiac sodium current.

Voltage-gated sodium channels (Na(V)s) are essential in propagating neuronal electrical impulse and triggering muscle contraction. In the heart, the Na(+) channel isoform Na(V)1.5 is strongly expressed and in the past was thought to be solely responsible for generating the cardiac Na(+) current (I(Na)). Recent studies, however, revealed that neuronal and skeletal muscle Na(+) channel isoforms are also expressed in the heart and contribute to cardiac I(Na). Amongst the findings is that many neuronal type Na(V)s are expressed in specific areas of the conduction system and ventricles. The contribution of these TTX-sensitive channels to normal cardiac function remains unclear but these data raise the possibility of a more prominent role of TTX-sensitive channels in conduction. Moreover, cardiac arrhythmias are commonly observed in many neuronal and musculoskeletal diseases despite their exclusive linkage to mutations in the neuronal and skeletal muscle sodium channel isoforms. The cause for these arrhythmias remains poorly understood. These recent findings indicate that neuronal and skeletal muscle sodium channels are expressed in areas of the heart that may be involved in the clinical phenotypes observed. The purpose of this review is to give an overview of the evidence for the presence of TTX-sensitive Na(V) isoforms in the heart and present the hypothesis brought forward so far for their direct role in cardiac function. These data demonstrate the promiscuous nature of the cardiac sodium current at the molecular level and should help us to bridge the gap that exists between our understanding of cardiac physiology and arrhythmias associated to brain and myotonic diseases.

Contribution of neuronal sodium channels to the cardiac fast sodium current INa is greater in dog heart Purkinje fibers than in ventricles.

OBJECTIVE: To determine the presence and the potential contribution of neuronal sodium channels to dog cardiac function. METHODS: We used a combination of electrophysiological (patch clamp), RT-PCR, biochemical and immunohistochemical techniques to identify and localize neuronal Na(+) channels in dog heart and determine their potential contribution to the fast sodium current. RESULTS: In all cardiac tissues investigated, Na(v)1.1, Na(v)1.2 and Na(v)1.3 transcripts were detected. In immunoblots, we found Na(v)1.1 and Na(v)1.2 proteins in the ventricle (V) and in Purkinje fibers (PF). Na(v)1.3 immunoblots suggested strong proteolytic activity against this isoform in the heart. Na(v)1.6 was not found in any of the tissues tested. Confocal immunofluorescence on cardiac myocytes showed that Na(v)1.1 was predominantly localized at the intercalated disks in V and PF and around the nucleus (V). Na(v)1.2 was only present at the Z lines (V). Consistent with the immunoblot data, an intense but diffuse intracellular staining was observed for Na(v)1.3. Na(v)1.6 fluorescence staining was faint and diffuse. Surprisingly, immunoblots indicated the presence of two Na(v)beta 2 variants: a 42-kDa protein that co-localized with Na(v)1.2 at the Z lines in V and a 34-kDa protein that co-localized with Na(v)1.1 at the intercalated disks in PF. In agreement with the biochemical data, electrophysiological results suggest that neuronal sodium channels generate 10+/-5% and 22+/-5% of the peak sodium current in dog ventricle and Purkinje fibers, respectively. CONCLUSIONS: Our results suggest that neuronal NaChs are more abundant in Purkinje fibers than in ventricles, and this suggests a role for them in cardiac conduction.