Potential Dependent Calcium Channels

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. 

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. 

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. 

Fig. 8. Effects of cannabinoids on synaptic transmission. Activation ofthe CBq receptor at the presynaptic axon terminal inhibits transmitter release from the synaptic vesicle. Three mechanisms can be involved in presynaptic inhibition X refers to unknown second messengers) inhibition of voltage-dependent calcium channels, activation of potassium channels and direct interference with the vesicle release machinery.TheCBi receptor can be activated by exogenous agonists, but also by the endocannahinoids anandamide (A 4) and 2-arachidonoylglycerol (2-AG i, which are released from the postsynaptic neuron by passive and/or facilitated diffusion. The synthesis of endocannahinoids is triggered by a depolarisation-induced ( / , membrane potential) calcium influx or by activation ofGq/n protein-coupled receptors...

Release of acetylcholine from the storage vesicles is initiated by an action potential that has traveled dovirn the axon to the presynaptic nerve membrane. This action potential leads to opening of voltage-dependent calcium channels, affording an influx of Ca and exocytotic release of acetylcholine into the synapse. The increase in intracellular Ca may induce fusion of acetylcholine storage vesicles virith the presynaptic membrane before release of the neurotransmitter. Each synaptic vesicle contains a quantum of acetylcholine one quantum represents betvireen 12,000 and 60,000 molecules of acetylcholine. A single action potential causes the release of several hundred quanta of acetylcholine into the synapse. 

Yessotoxin also potentiated the calcium uptake induced in lymphocytes exposed to maitotoxin, although in this case, the effect was insensitive to SKF 96365 [48]. In the presence of extracellular calcium, but not in its absence, yessotoxin decreased cellular levels of adenosine 3, 5 -cyclic monophosphate, owing to activation of phosphodiesterases [38]. hi isolated mitochondria, yessotoxin opened the permeability transition pore, a voltage-dependent calcium channel, at concentrations between 10 and 10 M. Again, this effect required the presence of calcium in the incubation medium [49]. In the presence of the chemotactic tripeptide A-formyl-Meth-Leu-Phe, yessotoxin increased the motihty of mussel immunocytes, an effect that was again inhibited by verapamil [50]. 

Tohns M, Weir E, Chesler E, Nelson D, From A. Pulmonary vascular tone is increased by a voltage-dependent calcium channel potentiator. J Appl Physiol 1986 60 942-948. 

Other drugs such as the neuroleptic, haloperidol, inhibit the induction of hsp70 mRNA in rodent neurons (Sharp et al.. 1992). Although this observation needs to be confirmed in the human population, it raises the possibility that an age-dependent defect in the production of HS proteins is exacerbated by a drug which is commonly used in demented elderly patients. The potential for certain pharmacologic agents to inhibit the HS response could increase the risk for untoward effects of atherosclerosis and hypoxia. A similar concern may be raised with certain calcium channel blockers which also have been found to reduce the synthesis of HS proteins in cardiac myocytes (Low-Friedrich and Schoeppe, 1991). 

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