Calcium channel inactivation gates

There are at least five different types of voltage-dependent Ca2+ channel molecules, differing in their gating kinetics, modes of Ca2+-inactivation and Ca2+-iregulation, and sensitivity to specific marine toxins [13] (see Ch. 6). The distinctions between the types of channel are of considerable interest because the different subtypes are believed to subserve different cellular functions. For example, the control of neurotransmitter release in peripheral sympathetic neurons appears to be under the predominant control of N-type calcium channels. 

Carbamazepine, valproate, and phenytoin enhance inactivation of voltage-gated sodium and calcium channels and limit the spread of electrical excitation by inhibiting sustained high-frequency firing of neurons. 

In a reversed type of approach, we used the pseudoreceptor modeling concept not to develop a tool for SAR predictions but to characterize two discrete ion channel modes on a molecular level [28]. For this purpose, a set of 13 well-characterized 1,4-dihydropyridine (DHP) derivatives with experimentally determined dissociation constants (Kf) for the voltage-gated calcium channel (VGCC) in the resting state (rs) and the open/inactivated state (is) were investigated (Table 5.2). 

Voltage-gated calcium channels mediate calcium influx that controls many functions such as contraction, secretion, neurotransmission, and gene expression in different cell types. In neurons and neuroblastoma cells, menthol inhibits calcium currents measured from low voltage-activated (LVA) and high voltage-activated (HVA) calcium channels in the concentration range of 0.1-1 mM [38, 39]. Additionally, menthol also accelerates inactivation phase of the calcium current from HVA calcium channels in a concentration-dependent manner and without major calcium influence [39, 40]. 

While Na channels rapidly inactivate as the membrane potential ( ,) approaches the equilibrium potential (0 mV), a second voltage-gated ion channel is activated that is carried by Ca " ions. Calcium channels cany that is responsible for the plateau phase of the AP (Fig. 1). These channels activate rapidly at approximately —40 to —20 mV and inactivate slowly. Calcium current can be approximated by the equation gca = Gca /where voltage-dependent rate constants (a and P) are determined for d and/. Many Ca " channel subtypes occur in the body. In the heart, at least 2 isoforms can be found the L and T types (see below for details). 

Figure 4. Whole-cell currents recorded from an axolotl vomeronasal receptor neuron in an epithelial slice. Currents were elicited by applying a series of voltage pulses, fiom -80 mV to +60 mV, in 10 mV increments. Vhoid = -80 mV. (A) Currents recorded in standard amphibian physiological saline, before any channel blockers were washed onto the slice. (B) Currents recorded 3 min after 10 pM tetrodotoxin (TTX) was washed onto the cell. TTX blocks voltage-gated sodium currents, revealing a second inward current. (C) Currents recorded 9 min after a solution containing both 10 pM TTX and 1 mM CoCk was washed onto the slice. Cobalt blocks calcium currents, demonstrating that the rapidly-inactivating inward current shown in panel B was carried by calcium.

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