Subcellular heterogeneity of sodium current properties in adult cardiac ventricular myocytes

Abstract

BACKGROUND Sodium channel α-subunits in ventricular myocytes (VMs) segregate either to the intercalated disc, or to lateral membranes, where they associate with region-specific molecules. OBJECTIVE To determine the functional properties of sodium channels as a function of their location in the cell. METHODS Local sodium currents were recorded from adult rodent VMs and Purkinje cells using the cell-attached macropatch configuration. Electrodes were placed either in the cell midsection (M), or cell end (area originally occupied by the intercalated disc; ID). Channels were identified as TTX-sensitive (TTX-S) or TTX-resistant (TTX-R) by application of 100 nM TTX. RESULTS Average peak-current amplitude was larger in ID than M, and largest at site of contact between attached cells. TTX-S channels were found only in M region of VMs, and not in Purkinje myocytes. TTX-R channels were found in M and ID, but their biophysical properties differed depending on recording location. Sodium current in rat VMs was upregulated by TNF-α. The magnitude of current increase was largest in M, but this difference was abolished by 100 nM TTX. CONCLUSIONS Our data suggest that: a) a large fraction of TTX-R (likely Nav1.5) channels in the M region of VMs are inactivated at normal resting potential, leaving most of the burden of excitation to TTX-R channels in the ID; b) cell-cell adhesion increases functional channel density at ID. c) TTX-S (likely non-Nav1.5) channels make a minimal contribution to sodium current under control conditions, but represent a functional reserve that can be upregulated by exogenous factors.

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

“…We next investigated whether the reduced whole‐cell I Na originated from the midsection (LM region) and/or the end of the cell (ID region). Consistent with previous findings,9 cell‐attached measurements in Sham cardiomyocytes revealed a lower I Na amplitude and a negative shift in steady‐state inactivation in the LM compared with the ID region (Figure 3A and 3B, Figure S1, and Table 2). In TAC cardiomyocytes, I Na amplitude was reduced in LM and ID by 50% and 40%, respectively (Figure 3A and 3B, Table 2), without any changes in gating parameters between Sham and TAC (Figure 3C through 3F, Table 2).…”

“…Sodium channel clusters in various cardiomyocyte microdomains exhibit distinct current amplitudes and gating properties 9. Studies in animal models have shown differential contribution of distinct subcellular sodium channel pools to global conduction in the heart 10, 11, 12.…”

“…Recent studies have shown that Na V 1.5 proteins cluster together, localize to distinct “pools” within subcellular microdomains of the cardiomyocyte, and associate with region‐specific proteins that regulate their function 7. In the intercalated disc (ID) region, Na V 1.5 colocalizes with N‐cadherin, ankyrin G, plakophilin‐2, and synapse‐associated protein 97, whereas Na V 1.5‐based channels located at the lateral membrane (LM) of the cardiomyocyte associate primarily with the dystrophin‐syntrophin complex 8, 9. Remodeling of region‐specific proteins may affect Na V 1.5 locally and lead to disturbances in I Na , conduction abnormalities, and arrhythmias 10, 11, 12, 13…”

PDZ Domain–Binding Motif Regulates Cardiomyocyte Compartment-Specific Na V 1.5 Channel Expression and Function

“…Recently, it was proposed that Na + channels in the midsection (ie, at the lateral membrane) of the rodent cardiomyocyte do not contribute significantly to AP propagation under physiological conditions. 22 In ΔSIV hearts, however, significant defects in impulse propagation were detected despite retention of Na V 1.5 expression at the intercalated disks, thus confirming a functional role for the Na V 1.5 lateral membrane pool and decreasing the sole contribution of Na V 1.5 intercalated disk channels to cardiac conduction. Moreover, the increase in anisotropy in ΔSIV mouse hearts indicates that the lateral membrane Na V 1.5 pool may play a role in longitudinal conduction, but that it has a more pronounced influence on transversal propagation.…”

Heterogeneity of ATP-sensitive K+ Channels in Cardiac Myocytes

“…At first sight, it is difficult to visualize the functional relationship between a structural element (the desmosome) and electrical events (arrhythmias). Recent data have helped to clarify the picture with the demonstration that some ion channels, such as the Na ϩ channel and some K ϩ channels (including Kv1.5 and Kir2.1), are enriched at the ICD (3)(4)(5). Moreover, there is growing evidence for interaction between desmosomal proteins and certain ion channels and that disruption of the desmosomal complex affects the function of these channels (4,6,7).…”