Calcium channel modulators, binding sites

The dihydropyridine- (DHP)-sensitive calcium channel purified from skeletal muscle is composed of five subunits al9 a2, P, y, and 8 (9-12). The cty subunit (molecular weight Mr 170 kD) forms a functional voltage-gated calcium channel (9, 13-15) and contains the binding sites for the three classes of calcium channel modulators 1,4-dihydropyridines (16), phenylal-kylamines, and benzothiazepines (17). The primary structure of the ax subunit was first elucidated from skeletal muscle (18) highly homologous sequences have since been cloned from cardiac muscle (13, 19, 20) and brain (21), aorta (22), and lung (23) tissue. 

FIGURE 10—24. Five modulatory sites on the N-methyW-aspartate (NMDA) receptor. The NMDA glutamate—calcium channel complex has multiple receptors in and around it, which act in concert as allosteric modulators. Three of these modulatory sites are located around the NMDA receptor. One of these modulatory sites is for the neurotransmitter glycine, another is for polyamines, and yet another is for zinc. Two of the modulatory sites are located inside or near the ion channel itself. The magnesium ion can block the calcium channel at one of these modulatory site, which is presumably inside the ion channel or close to it. The other inhibitory modulatory site, located inside the ion channel, is sometimes called the PCP site, since the psychotomimic agent phencylclidine (PCP) binds to this site. 

Beaumont V, Zucker RS (2000) Enhancement of synaptic transmission by cyclic AMP modulation of presynaptic Ih channels. Nat Neurosci 3 133 41 Beech DJ, Bernheim L, Hille B (1992) Pertussis toxin and voltage dependence distinguish multiple pathways modulating calcium channels of rat sympathetic neurons. Neuron 8 97-106 Benfenati F, Bahler M, Jahn R et al (1989a) Interactions of synapsin I with small synaptic vesicles distinct sites in synapsin I bind to vesicle phospholipids and vesicle proteins. J Cell Biol 108 1863-72... 

Accumulation of potassium within the cell by a cooperative process is a transmembrane event. However, there is also good evidence that movement of potassium ions through membrane channels is modulated by the binding of calcium ions at channel sites - the "plug in the bath" model (7). Membrane surface glycoproteins with polyanionic terminal strands offer a broad and powerful substrate for these cationic interactions. Competition between hydrogen and calcium ions at these sites has been modeled as the initial transductive step in excitation (8). 

One of the characteristics of protein calcium channels is their sensitivity to ablock by transition metal cations. Lanthanum is a particularly potent blocker. It is suggested that permeant and blocking ions compete for the common binding sites in the channels. The PolyP-PHB channel complexes are also blocked by transition metal cations in a concentration-dependent manner. A nearly complete block of single-channel currents was observed in the synthetic complexes at concentations > 0.1 mM La3+ (0.1 % of Ca2+) (Das et al., 1997). Evidently, PHB-PolyP complexes are versatile ion carriers whose selectivities may be modulated by small adjustments of the local pH. The results may be relevant to the physiological function of PHB-PolyP channels in bacteria and the role of PHBs and PolyPs in the Streptomyces lividans potassium channel (Das and Reusch, 2001). 

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