Channel L-type

First, their opening during somato-dendritic action potentials provides the source of the increased intracellular [Ca +] required to open Ca +-activated K+ channels — BK channels, to accelerate spike repolarisation, and SK channels, to induce spike-train adaptation and limit repetitive firing. The BK channels are activated (primarily) following entry of Ca + through L-type channels the source of Ca + for SK channel activation varies with different neurons, and may be either through L-type or N-type channels. 

Second, as in the ventricular muscle fibres of the heart, opening of L-type channels can generate sustained plateau potentials following the initial Na +-mediated action potential — for example, in the rhythmically firing neurons of the inferior olive (Fig. 2.7). 

A different but very interesting scenario involving L-type Ca channels is seen in skeletal muscle, where the major component of these Ca channels plays two roles. Skeletal muscle does not require extracellular Ca for excitation-contraction coupling, rather it utilizes Ca stored in the sarcoplasmic reticulum. The role of the L-type channel proteins as true Ca channels in skeletal muscle appears to be of secondary importance, but may be to provide Ca to the cells over longer periods of time. The main role of the L-type channel protein(s)... 

L-type Ca channels are the only Ca channels that have been extensively characterized at the biochemical level. The success in characterizing L-type channels was largely due to their rich pharmacology, and in particular to the availability of radio-labelled DHPs. However, a second major contributor to this successful characterization came from the seminal findings of Glossmann and colleagues [45] and Fosset, Lazdunski and colleagues [43] who identified skeletal muscle transverse tubule membranes as a relatively rich source of this rare membrane protein. 

For reasons that are not yet clear, skeletal muscle transverse (T)-tubule membranes contain 50-100-fold more high affinity DHP receptors than any other source yet identified [43,45]. Transverse tubule membranes contain 30-70 pmol/mg protein of DHP receptors that bind [ H]PN 200-100 with a of 0.1-0.2nM. The strategy utilized for the purification of L-type channels was similar to that used for the purification of other high affinity ligand binding proteins, and its success was predicted from the prior use of such an approach for the purification of other ion channels [54,55]. Thus the L-type channels were purified as high affinity DHP receptors, with the anticipation that the purified component(s) would constitute functional Ca channels. 

The purified L-type channels from skeletal muscle appear to be a multisubunit protein containing the products of four different and unrelated genes. A cartoon depicting some of the features of the purified protein is shown in Fig. 1. The subunits of the channel are commonly referred to as the ai, a2, ]8, y, and 8. These have been observed to migrate in a variety of SDS-polyacrylamide gels with apparent... 

Key findings that demonstrated that the 0 subunit is the essential component of L-type channels have come from studies of the channel activity of the expressed protein. Expression studies performed in mammalian liver fibroblasts have demonstrated that the oti subunit alone can form a channel [77] and contains the receptors for the DHPs, PAAs and diltiazem [64]. In very elegant studies using a mouse model of muscular dysgenesis it has been demonstrated that the ] subunit DNA can restore Ca currents and the charge movement that arises from the voltagesensing function of the channels to the mutant cells that normally lack these activities [21,78,79]. The restoration of these activities restores excitation-contraction coupling. Thus it is clear that the aj subunit is the major functional unit of L-type Ca channels. 

Fig, 2. Regulation of L-type channels by multiple second messenger systems. The cartoon is based on what is known or speculated about how L-type Ca channels might be regulated by proeesses that involve phosphorylation by different receptor mediated pathways. The actual receptors and number of pathways may vary in different cell types. The cartoon is loosely based on events that might occur in a cardiac cell. 

Regulation of L-type channels by phosphoprotein phosphatases As phosphorylation of certain Ca channels by protein kinases has been shown to... 

Somlyo What is Gd3+ doing to I. type channels, and what if arachidonic acid in smooth muscle inhibits L-type channels ... 

Taylor I should have said at the outset that all of these experiments are done with the L-type channels deliberately blocked by nifedipine or verapamil. 

Kotlikoff This is a different result, and would suggest coupling between the L-type channel and the BK channel. I think that Mark Nelson will discuss coupling between these channels independent of Ca2+ release. We see similar results with respect to the activation of spontaneous inward currents. 

Eisner Are you saying that most of the Ca2+ for contraction in the bladder doesn t come via the L-type channel ... 

The available Ca channel blockers exert their effects primarily at voltage-gated Ca channels of the plasma membrane. There are at least several types of channels—L, T, N, P/Q and R—distinguished by their electrophysiological and pharmacological characteristics. The blockers act at the L-type channel at three distinct receptor sites (Fig. 19.2). These different receptor interactions underlie, in part, the qualitative and quantitative differences exhibited by the three principal classes of channel blockers. 

L-type channel antagonists are the best developed and have been exploited for four primary clinical indications, including ... 

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