Tetrodotoxin‐blockable calcium currents in rat ventricular myocytes; a third type of cardiac cell sodium current

Abstract

Whole‐cell patch clamp currents from freshly isolated adult rat ventricular cells, recorded in external Ca2+ (Ca2+o) but no external Na+ (Ma4o), displayed two inward current components: a smaller component that activated over more negative potentials and a larger component (L‐type Ca2+ current) that activated at more positive potentials. The smaller component was not generated by Ca2+ channels. It was insensitive to 50 μm M2+ and 10 μm La3+, but suppressed by 10 μm tetrodotoxin (TTX). We refer to this component as ICa(TTx). The conductance–voltage, g(V), relation in Ca2+o only was well described by a single Boltzmann function (half‐maximum potential, V½, of –44.5; slope factor, k, of –4.49 mV, means of 3 cells). g(V) in Ca2+o plus Na4o was better described as the sum of two Boltzmann functions, one nearly identical to that in Ca2+o only (mean V½ of –45.1 and k of – 3.90 mV), and one clearly distinct (mean V½ of –35.6 and k of –2.31 mV). Mean maximum conductance for ICa(TTX) channels increased 23.7 % on adding 1 mm Na+o to 3 mm Ca2+o. ICa(TTx) channels are permeable to Na+ ions, insensitive to Ni2+ and La3+ and blocked by TTX. They are Na+ channels. I Ca(TTx) channels are distinct from classical cardiac Na+ channels. They activate and inactivate over a more negative range of potentials and have a slower time constant of inactivation than the classical Na+ channels. They are also distinct from yet another rat ventricular Na+ current component characterized by a much higher TTX sensitivity and by a persistent, non‐fast‐inactivating fraction. That ICa(TTx) channels activate over a more negative range of potentials than classical cardiac Na+ channels suggests that they may be critical for triggering the ventricular action potential and so of importance for cardiac arrhythmias.

Saxitoxin Blocks L-TypeICa

“…Based on the different effect of STX and TTX on L-type calcium channel, it is plausible that L-type calcium channels may bear a binding site for STX, but not for TTX. A different channel-mediated current, the TTX-blockable calcium current (I Ca,(TTX) ), has been reported in human atrial (Lemaire et al, 1995) and ventricular (Gaughan et al, 1999) myocytes, in guinea pig (Cole et al, 1997) and rat (Aggarwal et al, 1997) ventricular cells, and in neural preparations (Meves and Vogel, 1973;Akaike and Takahashi, 1992). The identity of the channel that conducts I Ca(TTX) is still controversial; however, it is possible that I Ca(TTX) is mediated by a subtype of a sodium channel and not a calcium channel (Aggarwal et al, 1997).…”

Identification of functional voltage-gated Na+ channels in cultured human pulmonary artery smooth muscle cells

“…However, in unpublished observations, we found that TTX did not significantly alter human PASMC E m (-41.2±2.6 mV, -46.2±3.1 mVin TTX, n=4, data not shown) indicating that Na + channel activity does not modulate E m in cultured normal human PASMC. [19] and triggers either further Ca 2+ release from the sarcoplasmic reticulum (SR) (causing contraction) or replenishes SR Ca 2+ pools by SERCA-mediated Ca 2+ re-uptake [1,29]. iii) TTX-sensitive Na + channels can conduct Ca 2+ ions in the absence of extracellular Na + or in the presence of trace doses of steroids such as ouabain and digoxin [6,29]; this can contribute to local and global Ca 2+ signaling, especially in heart failure patients treated with digoxin [29].…”

“…Ca 2+ re-uptake [1,29]. iii) TTX-sensitive Na + channels can conduct Ca 2+ ions in the absence of extracellular Na + or in the presence of trace doses of steroids such as ouabain and digoxin [6,29]; this can contribute to local and global Ca 2+ signaling, especially in heart failure patients treated with digoxin [29].…”

A Tale of Two (Calcium) Channels

“…It is, however, worthwhile to note that T-type channel expression was induced by growth hormone treatment in the experiments of Piedras-Renteria et al 17 By contrast, with the absence of T-type current in adult human heart, an LVA calcium current was first reported in human atria, 18 sharing some typical properties with sodium channels such as TTX sensitivity (designated ICa TTX ). Its description in rat 19 and guinea pig 20 myocytes indicated that it is not exclusively observed in diseased human cells. The study of Heubach et al 21 in this issue of Circulation Research demonstrates for the first time the coexistence of ICa TTX with ICa T in guinea pig ventricular myocytes.…”