Potential-dependent calcium

However, the studies on the calcium channel blockers remained centered even today around the l,4-dihydropyridine class. Since this class of compounds can also act as calcium channel activators, attention has always been drawn towards their structure-activity relationship studies. Attempts were made to differentiate in the mechanisms of their agonist and antagonist activities. On the basis of the force field and quantum mechanical calculations, Holtze and Marrer [51] discovered a imique area of the molecular potentials where Ca agonists and antagonists possess potential of opposite sign. These authors demonstrated that the molecular potential of a simple receptor site was reduced by interaction with calciiun channel activators and, on the contrary, increased by interaction with calcium channel blockers. These opposite effects probably could be the basis for the opposite actions of DHP enantiomers at the potential-dependent calcium channel. 

Hurwitz et al. (32) extended these ideas by giving evidence, again in a nonsecretory tissue, for two potential dependent calcium channels. These authors showed that the calcium channel associated with the phasic contraction of guinea pig ileal smooth muscle was blocked by lanthanum, but the calcium channel mediating the tonic contraction was not. In this system, both these channels were potential dependent. Hence, a variety of calcium channels may exist on cell surfaces. 

Verapamil (Class IV antiarrhythmic drug) is an effective agent for atrial or supraventricular tachycardia. A Ca++ channel blocker, it is most potent in tissues where the action potentials depend on calcium currents, including slow-response tissues such as the SA node and the AV node. The effects of verapamil include a decrease in heart rate and in conduction velocity of the electrical impulse through the AV node. The resulting increase in duration of the AV nodal delay, which is illustrated by a lengthening of the PR segment in the ECG, reduces the number of impulses permitted to penetrate to the ventricles to cause contraction. 

Fig. 4.1. Cellular model illustrating cell types in vascular wall involved in vasorelaxation induced by SERMs. Putative targets of SERMs are indicated within cyan tags. SERMs directly affect L-type VDCC, BK fil subunit in smooth muscle cells, and ER in endothelial cells. L-type VDCC L-type voltage-dependent calcium channel BK calcium-activated large conductance K+ channel PKG protein kinase G eNOS endothelial nitric oxide synthase GC soluble guanylate cyclase cGMP cyclic GM P V electrochemical membrane potential ER estrogen receptor. See text for further details...

Helliwell RM, Large WA 1997 Alphal-adrenoceptor activation of a non-selective cation current in rabbit portal vein by 1,2-diacyl-sn-glycerol. J Physiol 499 417-428 Hofmann F, Lacinova L, Klugbauer N 1999 Voltage-dependent calcium channels from structure to function. Rev Physiol Biochem Pharmacol 139 33—87 Hofmann T, Schaefer M, Schultz G, Gundermann T 2000 Transient receptor potential channels as molecular substrates of receptor-mediated cation entry. J Mol Med 78 14—25 Inoue R, Okada T, Onoue H et al 2001 The transient receptor potential protein homologue TRP6 is the essential component of vascular aj-adrenoceptor-activated Ca2+-permeable cation channel. Circ Res 88 325—332... 

Nomura, I., Kato, N., Kita, T., and Takechi, H. (2005). Mechanism of impairment of long-term potentiation by amyloid beta is independent of NMDA receptors or voltage-dependent calcium channels in hippocampal CA1 pyramidal neurons. Neurosci Lett 391, 1—6. 

D2R causes a potentiation of calcium-evoked arachidonic acid release through G-protein-dependent mechanisms involving PKC in a range of cells (Felder et al., 1991 Kanterman et al., 1991 Piomelli et al., 1991 Nilsson et al., 1998). 

With modest increase in intracellular ROS levels, activation of NF-kB takes place, which protects the cell against oxidative stress [45], Direct root of ROS participation in signal transduction from cell membrane to intracellular metabolic reactions were recently described. Among them - activation of potential-dependent K-channels and variation of membrane potential, inhibition of cellular protein phosphatases and restriction of activity of MAP-kinase [49]. Such view on intracellular role of ROS consider them as second messengers, which together with cyclic nucleotides, calcium ions, and other biologically active compounds provides adequate cell response to the outer signals. 

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