Na+ channel function, regulation, structure, trafficking and sequestration

Abstract

This paper is the second of a series of three reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation-contraction coupling and arrhythmias: Na(+) channel and Na(+) transport. The goal of the symposium was to bring together experts in the field to discuss points of consensus and controversy on the topic of sodium in the heart. The present review focuses on Na(+) channel function and regulation, Na(+) channel structure and function, and Na(+) channel trafficking, sequestration and complexing.

Figure 1

Late Na⁺ current in ventricular myocytes A, I_NaL recorded in a human ventricular myocyte using traditional square voltage clamp pulse from −120 mV (where Na⁺ channel availability is maximized) to −30 mV (where the peak of I_Na occurs; from Maltsev & Undrovinas, , with permission). B, I_NaL recorded under ^selfAP-clamp in guinea pig ventricular myocyte (from Horvath et al. , with permission). Notice that the I_NaL during AP can be clearly separated from the fast Na⁺ current at the onset of AP. I_NaL is sustained during the AP plateau phase, and increases as repolarization proceeds. This is because the driving force (E_m – E_Na) increases faster than the conductance declines during this phase. Nernst potentials for Na⁺ and K⁺ are shown (E_Na and E_K). I_NaL and K⁺ currents (I_Kr, I_Ks and I_K1) can be recorded from the same cell under ^selfAP-clamp Sequential Dissection.

Figure 2

NaV1.5 localization Upper panels show confocal images of mouse ventricular myocyte with dual immunofluorescence staining. Na_V1.5 (green) is expressed at the intercalated discs, T-tubules and lateral membrane. Punctate staining is most-likely at T-tubules. Syntrophin is only expressed at the lateral membrane where it co-localizes with Na_V1.5 (arrow in merge showing the yellow region of co-localization). Lower panels show myocytes from genetically modified mice (truncation of the last three residues of Na_V1.5 interacting with syntrophins and SAP97, ΔSIV) illustrating the reduction of Na_V1.5 expression exclusively at the lateral membrane (from Shy et al. , with permission).

Figure 3

Structure of a sodium channel Voltage-sensing domains (VSD-I, VSD-II, VSD-III, and VSD-IV) and pore-forming domain (PD) are labelled. Transmembrane segments S1–S6, and selectivity filter region pore helices P1 and P2 are labelled for domain I (blue). Each domain is a different colour.