Exploring the function and pharmacotherapeutic potential of voltage-gated Ca²⁺channels with gene-knockout models

The importance of the intracellular free Ca^* concentration as a key cellular signal transduction mechanism requires a tight control of Ca^* homeostasis thus enabling the independent regulation of free cytosolic Ca levels even within different cellular signaling compartments. In electrically excitable cells voltage-gated Ca^* channels (VGCCs) convert membrane potential changes into an intracellular Ca signal by mediating Ca ion entry along its electrochemical gradient during depolarization.^ The resulting intracellular Ca^* transient controls essential Ca ^-dependent physiological processes. These include neurotrans­ mitter release from fast chemical synapses in nerve terminals and from sensory cells, hormone release from endocrine cells, excitation-contraction coupling in heart, skeletal and smooth muscle and control of pacemaker activity in heart and neurons.^ Each of these specific tasks requires adjustment of Ca * channel fimction to its specific needs by targeting the channels to specific sites of the plasma membrane and by fine-tuning their opening and closing behaviour (gating). This explains why evolution generated a large number of different voltage-gated Ca^* channel types which can be distinguished based on their biophysical properties and the way they are regulated by second messenger pathways.^'^ Until now drugs and toxins specifically blocking the activity of individual channel types represented the most important tool to dissect their individual role for specific cellular fiinctions and facilitated their biochemical isolation and cloning.^' The different Ca^* channel types known to date, their specific modulators and proposed physiological roles are summarized in Table 1. Voltage-gated Ca^* channels form hetero-oligomeric complexes of several subunits (Fig. 1). This subunit structure is reviewed in detail in other articles in this body and therefore is not discussed in much detail here. Figure 1 illustrates that OLi subunits comprise the Ca^*-selective ion pore itself They determine most of the biophysical parameters (i.e. single channel conductance, activation and inactivation) and carry the drug and toxin interaction sites. So far ten different tti subunit isoforms, each of them undergoing fiirther fine-tuning by extensive alternative splicing, were identified in the human genome. Based on their different biophysical and pharmacological characteristics they give rise to 5 different Ca channel types (Table 1). Both p and a2-8 subunits (and to some extent also y-subunits, see below) are also required for proper channel targeting to the plasma membrane and fine-tuning of the gating properties of most al subunits. At least