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Two types of voltage-dependent [Ca.sup.2+] channels have been identified in heart: high ([I.sub.CaL]) and low ([I.sub.CaT]) voltage-activated [Ca.sup.2+] channels. In guinea pig ventricular myocytes, low voltage-activated inward current consists of [I.sub.CaT] and a tetrodotoxin (TTX)-sensitive [I.sub.Ca] component ([I.sub.Ca(TTX)]). In this study, we reexamined the nature of low-threshold [I.sub.Ca] in dog atrium, as well as whether it is affected by [Na.sup.+] channel toxins. [Ca.sup.2+] currents were recorded using the whole-cell patch clamp technique. In the absence of external [Na.sup.+], a transient inward current activated near -50 mV, peaked at -30 mV, and reversed around +40 mV (HP = -90 mV). It was unaffected by 30 [micro]M TTX or micromolar concentrations of external [Na.sup.+], but was inhibited by 50 [micro]M [Ni.sup.2+] (by ~90%) or 5 [micro]M mibefradil (by ~50%), consistent with the reported properties of [I.sub.CaT]. Addition of 30 [micro]M TTX in the presence of [Ni.sup.2+] increased the current approximately fourfold (41% of control), and shifted the dose-response curve of [Ni.sup.2+] block to the right ([IC.sub.50] from 7.6 to 30 [micro]M). Saxitoxin (STX) at 1 [micro]M abolished the current left in 50 [micro]M [Ni.sup.2+]. In the absence of [Ni.sup.2+], STX potently blocked [I.sub.CaT] ([EC.sub.50] = 185 nM) and modestly reduced [I.sub.CaL] ([EC.sub.50] = 1.6 [micro]M). While TTX produced no direct effect on [I.sub.CaT] elicited by expression of h[Ca.sub.v] 3.1 and h[Ca.sub.v]3.2 in HEK-293 cells, it significantly attenuated the block of this current by [Ni.sup.2+] ([IC.sub.50] increased to 550 [micro]M [Ni.sup.2+] for [Ca.sub.v]3.1 and 15 [micro]M [Ni.sup.2+] for [Ca.sub.v]3.2); in contrast, 30 [micro]M TTX directly inhibited h[Ca.sub.v]3.3-induced [I.sub.CaT] and the addition of 750 [micro]M [Ni.sup.2+] to the TTX-containing medium led to greater block of the current that was not significantly different than that produced by [Ni.sup.2+] alone. 1 [micro]M STX directly inhibited [Ca.sub.v]3.1-, [Ca.sub.v]3.2-, and [Ca.sub.v]3.3-mediated [I.sub.CaT] but did not enhance the ability of [Ni.sup.2+] to block these currents. These findings provide important new implications for our understanding of structure-function relationships of [I.sub.CaT] in heart, and further extend the hypothesis of a parallel evolution of [Na.sup.+] and [Ca.sup.2+] channels from an ancestor with common structural motifs.

Author(s): Shana L. Geffeney (corresponding author) [1]; Esther Fujimoto [1, 3]; Edmund D. Brodie, III [2]; Edmund D. Brodie, Jr [1]; Peter C. Ruben [1] Understanding the molecular genetic basis [...]

Voltage-gated sodium (Nav) channels initiate action potentials in excitable tissues. Altering these channels’ function can lead to many pathophysiological conditions. Nav channels are composed of several functional and structural domains that could be targeted pharmacologically as potential therapeutic means against various neurological conditions. Mutations in Nav channels have been suggested to underlie various clinical syndromes in different tissues and in association with conditions ranging from epileptic to muscular problems. Treating those mutations that increase the excitability of Nav channels requires inhibitors that could effectively reduce channel firing. The main non-psychotropic constituent of the cannabis plant, cannabidiol (CBD), has recently gained interest as a viable compound to treat some of the conditions that are associated with Nav malfunctions. In this review, we discuss an overview of Nav channels followed by an in-depth description of the interactions of CBD and Nav channels. We conclude with some clinical implications of CBD use against Nav hyperexcitability based on a series of preclinical studies published to date, with a focus on Nav/CBD interactions. [ABSTRACT FROM AUTHOR]