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• W2029254321 abstract "Studies of calcium channel function have been marked throughout their history by the need to classify the different functional subtypes of calcium channel current that can be observed within a single cell. This is particularly the case for neurones where diverse calcium channels subserve different roles within the cell. The earliest classification divided channel types according to their threshold for activation. Thus channels activated by small depolarizations from the resting membrane potential were named ‘low voltage activated’ while stronger depolarizations recruited the ‘high voltage activated’ channels. It rapidly became clear that such a simple subdivision was inadequate for describing a heterogeneous current that showed a wide range of biophysical properties. A more robust description of the different channel subtypes found in neurones and other cells was provided by analysis of single channel records from avian sensory neurones. Based on activation threshold, channel conductance, inactivation properties and sensitivity to dihydropyridine agonists it was possible to distinguish three separate and distinct channel subtypes designated L-, N- and T-type Ca2+ channels (Nowycky et al. 1985). These distinctions between the channel subtypes were aided by pharmacological tools. Organic calcium channel antagonists appeared to selectively block L-type channels, while a study of venom fractions from fish-hunting marine snails culminated in the discovery that ω-conotoxin GVIA was a selective inhibitor of N-type calcium channels. Toxins were also useful in identifying new channel subtypes. Llinas et al. (1989) identified a novel channel that appeared to be the main Ca2+ channel expressed in cerebellar Purkinje neurones and labelled it the P-type channel. This channel could be selectively blocked by the spider toxin ω-agatoxin IVA. Another channel with properties very similar to the P-type channel was subsequently described in cerebellar granule neurones by Randall & Tsien (1995). The Q-type channel was distinguished from P-type channels by activation threshold, inactivation rate and lower sensitivity to block by ω-agatoxin GIVA. Finally, the R-type Ca2+ channel current was described, displaying the inactivation properties of the low-voltage-activated ‘T’-type current but which required strong depolarizations for activation and was blockable by a toxin isolated from tarantula venom (Ca2+ channel subtypes reviewed by Catterall et al. 2005).The apparent complexity of Ca2+ channel pharmacology is even greater when the molecular diversity of calcium channels is considered. Ten genes encoding the pore-forming α1 subunit of Ca2+ channels have so far been discovered and these can be divided into three subfamilies. One family corresponds to the L-type channels, another to N-, P-, Q- and R-type channels and the third family comprises the T-type channels. Interestingly, the P- and Q-type currents are derived from the same gene encoding the α1 subunit. Pharmacological differences appear to mainly be due to alternative splicing. Matters are further complicated by the existence of several accessory subunits which can modify the biophysical characteristics of the channel and their expression levels. Nonetheless, pharmacological sensitivity appears to be conferred by the α1 subunit and it has been considered a truism that the defining compounds and toxins that selectively block a functional current are specific for each.The recent highly interesting findings from Maria Usowciz's group in this issue of The Journal of Physiology indicate that Ca2+ channel pharmacology is not as clear-cut as previously thought (Tringham et al. 2007). The key observation is the effect of the archetypal dihydropyridine Ca2+ channel agonist (–)-(S)-BayK8644, on the Ca2+ channel current in adult cerebellar Purkinje neurones, the cell type in which the P-type channel was first described. This compound, originally used to help define L-type Ca2+ channel activity, appears to inhibit a current sensitive to block by ω-agatoxin IVA. Block by (–)-(S)-BayK8644 is potent and stereoselective, and affects approximately 66% of what would normally have been defined as the P-type current. Surprisingly there appears to be no sensitivity of the channel to other dihydropyridines such as the channel blocker nimodipine. There have been previous reports of dihydropyridine block of N-, P- and Q-type channels (e.g. Mansvelder et al. 1996); however, these generally involved the use of much higher concentrations of nimodipine than those used here.It is still not clear what the molecular basis for this pharmacologically distinct current is. Alternative splicing is possible at a number of sites throughout the sequence of the α1 subunit of the calcium channel (see Jurkat-Rott & Lehmann-Horn, 2003 for review). Just as splice variation can alter sensitivity of the CaV2.1 (P/Q) channel to ω-agatoxin IVA, it is possible that a splice variant may be responsible for conferring the property of block by (–)-(S)-BayK8644 on the P-type channel. A less likely possibility is an involvement of an accessory subunit or of an action upon a modulatory protein associated with the channel. A resolution of these possibilities requires careful investigation of recombinant channels. What is now clear is that caution needs to be taken when using pharmacological agents to define channel subtypes in native systems. Compounds that have been described as ‘specific’ should be considered ‘selective’ and conclusions regarding channel expression profile in some cell types may need to be reinvestigated or revised. However, while this finding adds to the complexity of neuronal calcium pharmacology, it opens the possibility of greater specificity in directing pharmacological interventions at specific brain regions or specific cell types within a region." @default.
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• W2029254321 date "2007-01-26" @default.
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• W2029254321 title "Calcium channel subtypes - another layer of complexity to an already intricate story" @default.
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• W2029254321 doi "https://doi.org/10.1113/jphysiol.2006.126144" @default.
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