Calcium channels presynaptic

In the venom of C. geographus and other fish-hunting species, the conotoxins isolated so far can be divided into three major classes (1-4) o -conotoxms which block neuronal calcium channels at the presynaptic terminus of the neuromuscular junction, a-conotoxins which inhibit the acetylcholine receptor at the postsynaptic terminus, and x-conotoxins which block Na channels on the muscle membrane. 

Figure 21.5 Mechanisms of opioid analgesia at the spinal level. Action potentials in nociceptive afferent fibres invade the terminal and by opening calcium channels (L, N and P-type) cause the release of glutamate and peptides that further transmit pain subsequent to activation of their postsynaptic receptors. Presynaptic opioid receptor activation (mu- and delta-mediated effects have been most clearly shown) opens potassium channels which hyperpolarise the terminal, so reducing transmitter release and inhibiting the postsynaptic neuron...

Boehm, S. and Huck, S. Inhibition of N-type calcium channels the only mechanism by which presynaptic alpha 2-autoreceptors control sympathetic transmitter release. Eur J. Neurosci. 8 1924-1931,1996. 

Reuter H (1996) Diversity and function of presynaptic calcium channels in the brain. Curr Op Neurobiol 6 331-337... 

A similar optimization of reaction conditions was required for oxidation of PLTX-II (13) (Scheme 8). This presynaptic calcium channel blocker is a 44-residue peptide containing five intramolecular disulfide bonds and an O-palmitoylated Thr amide at the carboxy-termi-nusJ83 ... 

Scheme 8 Presynaptic Calcium Channel Blocker PLTX-IlI791...

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.

Cypros Pharm. Corp. describes the use of polyguanidino derivatives as presynaptic N- and P/Q-type calcium channel blockers for i.v. (or i.c.v.) administration (Marangos et al. (Cypros Pharmaceutical Corp.), W09836743). Compound 5 was administered to gerbils (7.5 mg/kg i.v.) prior to bilateral carotid occlusion. After 72 h the animals were sacrificed. Brains were perfusion-fixed and sections were stained to enable quantitative cell counts of live and dead neurons. The number of damaged neurons in the subiculum was 91.5 compared to 214 for a control treated with saline. It has been claimed that this compound can be used for the treatment of neuropathic pain and for the protection of neurons from excitatory damage under conditions of cerebral hypoxia. 

Marangos, P.J., Sullivan, B.W., Wiemann, T., Danks, AM., Sragovicz, M., Makings, L.R. (Cypros Pharmaceutical Corp.), Neuroprotective poly-guanidino compounds which block presynaptic N and P/Q calcium channels, W09836743 (1998). 

It has been demonstrated that cannabinoids act to suppress action potential-evoked calcium rises in the presynaptic terminal, thereby decreasing transmitter release. The action potential-evoked rise in intraterminal calcium was decreased by postsynaptic depolarization. This postsynaptic depolarization induced reduction of presynaptic calcium was prevented by application of antagonists to the CBi receptor (Kreitzer and Regehr, 2001). Cannabinoid-induced decreases in synaptic transmission have been shown to result from an inhibition of N- and P/Q-type calcium channels, the subtypes through which calcium influx occurs during evoked transmitter release (Twitchell et al., 1997). 

Once an electrical impulse invades the presynaptic axon terminal, it causes the release of chemical neurotransmitter stored there (Fig. 1—3). Electrical impulses open ion channels, such as voltage-gated calcium channels and voltage-gated sodium channels, by changing the ionic charge across neuronal membranes. As calcium flows into the presynaptic nerve, it anchors the synaptic vesicles to the inner membrane of the nerve terminal so that they can spill their chemical contents into the synapse. The way is paved for chemical communication by previous synthesis and storage of neurotransmitter in the first neuron s presynaptic axon terminal. 

L-type calcium channels are the primary trigger for excitation-contraction (EC) coupling in cardiac, skeletal, and smooth muscles (Bean, 1989). They are also found in most central and peripheral neurons where they in part control calcium-dependent gene expression, as well as in endocrine cells and many types of non-excitable cells where they contribute to a variety of processes including exocytotic release. Unlike most synapses in the brain and spinal cord that rely on P/Q- and N-type calcium channels for neurotransmitter release, (Wheeler et al., 1994), the presynaptic terminals in photoreceptor cells rely on the Cav1.4 (a1F) L-type calcium channel for mediating glutamate release (Tachibana et al., 1993 Nachman-Clewner et al., 1999). Photoreceptor neurotransmission is atypical first,... 

As described in Chapter 4, regulatory G proteins act as an intermediate link between receptor activation and the intracellular effector mechanism that ultimately causes a change in cellular activity. In the case of opioid receptors, these G proteins interact with three primary cellular effectors calcium channels, potassium channels, and the adenyl cyclase enzyme.27 At the presynaptic terminal, stimulation of opioid receptors activates G proteins that in turn inhibit the opening of calcium channels on the nerve membrane.65 Decreased calcium entry into the presynaptic terminal causes decreased neurotransmitter release because calcium influx mediates transmitter release at a chemical synapse. At the postsynaptic neuron, opioid receptors are linked via G proteins to potassium channels, and... 

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... 

Presynaptic Calcium Channels Structure, Regulators, and Blockers... 

Regulation of Presynaptic Calcium Channel Activity by Protein Kinases. 61... 

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