Voltage-sensitive calcium channels VSCC

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. 

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. 

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.

Dopamine Dl receptor activation enhances NMDA-mediated excitatory responses (Cepeda et al., 1993 Cepeda and Levine, 1998). The modulatory actions of dopamine on NMD A receptor mediated responses are reduced in Dl deficient mice (Levine et al., 1996a), supporting a specific role for Dl receptors in enhancement. However, this enhancement involves a complex interplay of actions both on the NMDA receptors and also on the voltage-sensitive calcium channels (VSCC). In particular, the activation of VSCC conductances on the distal dendrites contributes to the enhancement of NMDA currents by dopamine. This mechanism of enhancement involves increased regenerative amplification of synaptic responses by increased VSCC currents (Cepeda et al., 1993, 1998 Cepeda and Levine, 1998). Synaptic responses may also be increased directly by... 

Excessive calcium entry into depolarized neurons contributes significantly to neuronal injury. Voltage-sensitive calcium channels (VSCCs) regulate, among other functions, cellular excitability and neurosecretory activity, functions implicit in epileptogenic events... 

A key feature of excitotoxic cell death involves an imbalance in Ca " homeostasis and demonstration of the activation of L-type voltage-sensitive calcium channels (VSCCs) allowing entry of Ca " that is localized to vulnerable brain regions (Hazell et al. 1998) (Figure 32.3). Along with the rise in... 

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.

Fig. 3 Mechanisms involved in presynaptic inhibition through P2Y receptors. P2Yi 2,4,12 receptors may couple to PTX-sensitive proteins and mediate voltage-dependent inhibition of calcium currents by direct interaction of the Py subunits with the N-type VSCC (1). The P2Yi, 2,4 receptor subtypes may also couple to PTX-insensitive Gq/n proteins and mediate voltage-independent inhibition of Ca2+ currents by (2) direct interaction of G protein Py subunits with the channel or (3) activation of phospholipase C (PLC), causing depletion of membrane phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2).

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