Voltage-sensitive calcium

Stimulation of mAChRs also results in the activation or inhibition of a large number of ion channels [5]. For example, stimulation of Mi receptors leads to the suppression of the so-called M current, a voltage-dependent Recurrent found in various neuronal tissues. M2 receptors, on the other hand, mediate the opening of cardiac Ikcacii) channels, and both M2 and M4 receptors are linked to the inhibition of voltage-sensitive calcium channels [5]. 

Although there is no evidence that the neuronal degeneration of AzD results, as in cardiovascular ischaemia, from the excitotoxicity of increased intracellular Ca +, some calcium channel blockers have been tried in AzD. They have had little effect but surprisingly a pyrrolidone derivative nefiracetam, which opens L-type voltage-sensitive calcium channels (VSCCs) reduces both scopolamine- and )S-amyloid-induced impairments of learning and memory in rats (Yamada et al. 1999). This effect can be overcome by VSCC antagonists, but nefiracetam has not been tried in humans. 

Neurotransmitter release induced by potassium-dependent depolarization is a physiologically relevant way to investigate pyrethroid effects on calcium-dependent neurotransmitter release since this process is independent of voltage-sensitive sodium channels [71]. Furthermore, potassium-stimulated calcium influx and subsequent neurotransmitter release by synaptosomes is blocked by a variety of voltage-sensitive calcium channel antagonists but not by TTX [4, 71, 72]. 

Shafer TJ, Meyer DA (2004) Effects of pyrethroids on voltage-sensitive calcium channels a critical evaluation of strengths, weaknesses, data needs, and relationship to assessment of cumulative neurotoxicity. Toxicol Appl Pharmacol 196 303-318... 

Symington SB, Clark JM (2005) Action of deltamethrin on N-type (Cav2.2) voltage-sensitive calcium channels in rat brain. Pestic Biochem Physiol 82 1-15... 

Mutanguha EM, Valentine ZH, Symington SB (2010) Pyrethroid inhibition of a human T-type voltage-sensitive calcium channel is structural specific and concentration -dependent. 49th Annual Society of Toxicology, Salt Lake City, UT... 

The sequence of events that result in neurotransmission of information from one nerve cell to another across the s)mapses begins with a wave of depolarization which passes down the axon and results in the opening of the voltage-sensitive calcium charmels in the axonal terminal. These charmels are frequently concentrated in areas which correspond to the active sites of neurotransmitter release. A large (up to 100 M) but brief rise in the calcium concentration within the nerve terminal triggers the movement of the synaptic vesicles, which contain the neurotransmitter, towards the synaptic membrane. By means of specific membrane-bound proteins (such as synaptobrevin from the neuronal membrane and synaptotagrin from the vesicular membrane) the vesicles fuse with the neuronal membrane and release their contents into the synaptic gap by a process of exocytosis. Once released of their contents, the vesicle membrane is reformed and recycled within the neuronal terminal. This process is completed once the vesicles have accumulated more neurotransmitter by means of an energy-dependent transporter on the vesicle membrane (Table 2.3). 

Schematic illustration of a generalized cholinergic junction (not to scale). Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (CHT). This transporter can be inhibited by hemicholinium drugs. In the cytoplasm, acetylcholine is synthesized from choline and acetyl -A (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine is then transported into the storage vesicle by a second carrier, the vesicle-associated transporter (VAT), which can be inhibited by vesamicol. Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle. Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft (see text). This step can he blocked by botulinum toxin. Acetylcholine s action is terminated by metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. SNAPs, synaptosome-associated proteins VAMPs, vesicle-associated membrane proteins.

An action potential in the presynaptic fiber propagates into the synaptic terminal and activates voltage-sensitive calcium... 

Bowersox, S.S., Gadbois, Th., Singh, T., Pettus, M., Wang, Y.-X., Luther, R.R. Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX - 111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain, J. Pharmacol. Exper. Ther. 1996, 279, 1243-1249. 

Brose, W.G., Gutlove, D.P., Luther, R.R., Bowersox, S.S., McGuire, D. Use of intrathecal SNX-111, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain, Clin. J. Pain, 1997, 13, 256-259. 

Malmberg, A.B. and Yaksh, T.L. Voltage-sensitive calcium channels in spinal nociceptive processing Blockade of N- and P-type channels inhibits formalin-induced nociception, J. Neurosci. 1994, 14, 4882-4890. 

Wang, Y-X., Gao, D., Pettus, M., Phillips, C., Bowersox, S.S. Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive calcium channels, with morphine on nociception in rats, Pain 2000, 84, 271-281. 

Ekinci, F. J., Malik, K. U., and Shea, T. B. (1999). Activation of the L voltage-sensitive calcium channel by mitogen-activated protein (MAP) kinase following exposure of neuronal cells to beta-amyloid. MAP kinase mediates beta-amyloid-induced neurodegeneration. J Biol Chem 274, 30322-30327. 

CPZ (9) also showed some inhibitory effects with respect to the calcium current produced by combined expression of aiE and (>3 subunits of voltage-sensitive calcium channels (VSCCs) [269]. The authors of this article suggested that this effect could be the result of either direct interaction of the drug with channel protein or indirect alteration of the properties of the lipid bilayer surrounding the VSCC molecules. 

Schematic diagram of a generalized noradrenergic junction (not to scale). Tyrosine is transported into the noradrenergic ending or varicosity by a sodium-dependent carrier (A). Tyrosine is converted to dopamine (see Figure 6-5 for details), which is transported into the vesicle by a carrier (B) that can be blocked by reserpine. The same carrier transports norepinephrine (NE) and several other amines into these granules. Dopamine is converted to NE in the vesicle by dopamine-B-hydroxylase. Release of transmitter occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. Fusion of vesicles with the surface membrane results in expulsion of norepinephrine, cotransmitters, and dopamine-13-hydroxylase.

An action potential in the presynaptic fiber propagates into the synaptic terminal and activates voltage-sensitive calcium channels in the membrane of the terminal (Figure 6-3). The calcium channels responsible for the release of transmitter are generally resistant to the calcium channelblocking agents discussed in Chapter 12 Vasodilators the Treatment of Angina Pectoris (verapamil, etc) but are sensitive to blockade by certain marine toxins and metal ions (Tables 12-4 and 21-1). Calcium flows into the terminal, and the increase in intraterminal calcium concentration promotes the fusion of synaptic vesicles with the presynaptic membrane. The transmitter contained in the vesicles is released into the synaptic cleft and diffuses to the receptors on the postsynaptic... 

Reynolds IJ, Wagner JA, Snyder SH, Thayer SA, Olivera BM, Miller RJ (1986) Brain voltage-sensitive calcium channel subtypes differentiated by omega-conotoxin fraction GVIA. Proc Natl Acad Sci U S A 83 8804-7... 

Although noradrenergic terminals normally contain too little dopamine for presynaptic dopamine heteroreceptors to become activated, and despite the fact that the hippocampus is only sparsely innervated by dopaminergic fibers (Bischoff et al. 1979), the release of [3H]-noradrenaline in rabbit (Jackisch et al. 1985) and rat (Monnet 2002) hippocampus was inhibited by endogenous dopamine as shown by the facilitatory effect of D2 antagonists. Voltage-sensitive calcium channels seem to play a role in the dopaminergic inhibition of noradrenaline release (Monnet 2002). 

Fig. 1 Mechanisms involved in presynaptic inhibition through Ai adenosine receptors (AiAR). Ai AR couple to PTX-sensitive Gl (, proteins. Two pathways are then mediated by G Py subunits (1) to N-type voltage-sensitive calcium channels (VSCC) and, to a smaller degree, P/Q-type VSCC, leading to voltage -dependent inhibition, and (2) to the exocytotic machinery, leading to inhibition by a mechanism independent of calcium currents.

Fig. 2 Mechanisms involved in presynaptic facilitation through A2 adenosine receptors. A2A and A2B adenosine receptors (A2aAR, A2B AR), by coupling to Gs, activate adenylate cyclase and protein kinase A (PKA). This may (1) influence SNARE proteins or (2) enhance calcium currents through P-type voltage-sensitive calcium channels (P-VSCC). A2aAR may also couple to Gq, leading to activation of a protein kinase C (PKC) pathway. This may (3) enhance calcium currents through N-VSCC, (4) influence SNARE proteins, (5) promote the PKA pathways or (6) remove an ongoing Gj/0 mediated inhibition of release.

Mode of action. Clobazam, like most of the benzodiazepines in clinical use, acts as an agonist on the benzodiazepine receptor site and thereby enhances GABAergic transmission. It is uncertain why the action of clobazam differs from the conventional benzodiazepines but it is possible that it could reflect differential binding to the GABA-A receptor sub-units. In addition to its action on GABA receptors, clobazam also reduced voltage-sensitive calcium ion conductance and sodium channel conductance. 

ADOl, voltage-sensitive calcium Agriosphodrus dohmi... 

The w-conotoxins, which bind to voltage-sensitive calcium channel, are perhaps the most extensively studied members of the conotoxin family and comprise a six-cysteine/four-loop framework. They are exemplified in Fig. 23 by our... 

Release of acetylcholine When an action potential propagated by the action of voltage-sensitive sodium channels arrives at a nerve ending, voltage-sensitive calcium channels in the presynaptic membrane open, causing an increase in the concentration of intracellular calcium. Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and release of acetylcholine into the synapse. This release is blocked by botulinum toxin. By contrast, black widow spider venom causes all of the cellular acetylcholine stored in synaptic vesicles to spill into the synaptic gap. 

---