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Role of Ca V 2.2 channels in synaptic transmission. Ca V 2.2 channels are expressed in presynaptic membrane of afferent nociceptive neurons. They form signaling complex with synaptic vesicles releasing glutamate. Depolarization of presynaptic membrane by incoming action potential results in activation of Ca V 2.2 channels. Calcium entry through these channels activates exocytosis and glutamate release. Glutamate (Glu) activates corresponding receptors in postsynaptic membrane of dorsal horn neuron. Cations entering through NMDA and AMPA receptors depolarize postsynaptic membrane and initiate signaling to the brain.

Role of Ca V 2.2 channels in synaptic transmission. Ca V 2.2 channels are expressed in presynaptic membrane of afferent nociceptive neurons. They form signaling complex with synaptic vesicles releasing glutamate. Depolarization of presynaptic membrane by incoming action potential results in activation of Ca V 2.2 channels. Calcium entry through these channels activates exocytosis and glutamate release. Glutamate (Glu) activates corresponding receptors in postsynaptic membrane of dorsal horn neuron. Cations entering through NMDA and AMPA receptors depolarize postsynaptic membrane and initiate signaling to the brain.

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N-type or CaV2.2 high-voltage activated calcium channels are distinguished by exclusively neuronal tissue distribution, sensitivity to ω-conotoxins, prominent inhibition by G-proteins, and a unique role in nociception. Most investigated modulatory pathway regulating the CaV2.2 channels is G-protein-coupled receptor-activated pathway leading to curr...

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... interaction stabilizes membrane localization of Ca V 2.2 channels in close proximity to synaptic vesicles. Incoming action potentials activate large temporally precise calcium influx through Ca V 2.2 channels and activate release of neurotransmitters like glutamate or substance P ( Weber et al. 2010) ensuring transmission of peripheral signals to the brain (Figure 1). This pathway conveys various sensory modalities from peripheral sensory neurons including pain, itch, touch, and perception of body muscle tension ( Bourinet et al. 2014). ...
Context 2
... their specific involvement in nociception and lack of exclusive role in other physiological processes inhibition of Ca V 2.2 channels is a promising strategy for treatment of severe chronic pain. Four possible scenarios are available: i) direct inhibition of the channel; ii) inhibition of N-type calcium current by activation of GPCR; iii) inhibition of membrane targeting of the channel protein; iv) disruption of signaling protein complex (Figure 1). ...

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... The N-type Ca 2+ channel voltage-gated calcium channel (Ca V )2.2, which induces peripheral neuron neurotransmission [51], is degraded via the UPS to maintain the precise modulation of its expression [52,53]. For example, the overexpression of Parkin, which is an E3 ligase, decreases the current of Ca V 2.2 through proteasome-induced degradation [52], and proteasome inhibition through MG-132 increases the current of Ca V 2.2 [53]. ...
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... Unlike the low-threshold calcium channels, the high-threshold voltage-gated calcium channels are heteromultimeric proteins [67]. Ca V 2.2 channels consist of principal α1 and auxiliary β, and α 2 δ subunits encoded by multiple genes [55]. ...
... The α 2 δ1 was shown to be necessary for the trafficking of the channel complex into the plasma membrane in DRG neurons [100]. Modulatory effects of all auxiliary subunits are predominantly of gain-of-function type [55]. ...
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Noxious stimuli like cold, heat, pH change, tissue damage, and inflammation depolarize a membrane of peripheral endings of specialized nociceptive neurons which eventually results in the generation of an action potential. The electrical signal is carried along a long axon of nociceptive neurons from peripheral organs to soma located in dorsal root ganglions and further to the dorsal horn of the spinal cord where it is transmitted through a chemical synapse and is carried through the spinal thalamic tract into the brain. Two subtypes of voltage-activated calcium play a major role in signal transmission: a low voltage-activated CaV3.2 channel and a high voltage-activated CaV2.2 channel. The CaV3.2 channel contributes mainly to the signal conductance along nociceptive neurons while the principal role of the CaV2.2 channel is in the synaptic transmission at the dorsal horn. Both channels contribute to the signal initiation at peripheral nerve endings. This review summarizes current knowledge about the expression and distribution of these channels in a nociceptive pathway, the regulation of their expression and gating during pain pathology, and their suitability as targets for pharmacological therapy.
... [4,5] NP activates N-methyl-D-aspartate (NMDA) receptors especially NR2B, [6][7][8] the capsaicin receptor transient receptor potential channels especially TRPV1, also known as vanilloid receptor, [9][10][11] N-type or high-voltage activated calcium channels especially CaV2.2 is associated with inflammation. [12][13][14] Recent studies have suggested that NR2B, TRPV1 and voltage-gated calcium (CaV2.2) channels are the emerging targets for treating neuropathic pain. [10,12,13] Macrophages, chemokines, cytokines (TNF-α, IL-6, IL-1β) are the key players of inflammation in peripheral nerve injuries. ...
... [12][13][14] Recent studies have suggested that NR2B, TRPV1 and voltage-gated calcium (CaV2.2) channels are the emerging targets for treating neuropathic pain. [10,12,13] Macrophages, chemokines, cytokines (TNF-α, IL-6, IL-1β) are the key players of inflammation in peripheral nerve injuries. [15] Sommer et al. [16] also reported that anti-inflammatory agents targeting these key players would provide a better therapeutic strategy in neuropathic pain. ...
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... Modulation of the N-type Ca 2+ channels by G-proteins is most extensively studied and was recently reviewed by several authors [20][21][22][23]. To describe the alteration of channel gating upon interaction with G-proteins, a model of "willing" and "reluctant" gating states was introduced [24,25]. ...
... Schematic depiction of the role of presynaptic Ca V 2.2 in signal transmission in a nociceptive synapse. Modified from[22] with permission. ...
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... Modulation of the N-type Ca 2+ channels by G-proteins is most extensively studied and was recently reviewed by several authors [20][21][22][23]. To describe the alteration of channel gating upon interaction with G-proteins, a model of "willing" and "reluctant" gating states was introduced [24,25]. ...
... Schematic depiction of the role of presynaptic Ca V 2.2 in signal transmission in a nociceptive synapse. Modified from[22] with permission. ...
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... Ca v 2.2 channel subtypes are known as N-type because they are exclusively neuronal and express a Ca ++ current component that is different from L-type (Ca v 1.1-Ca v 1.4) or T-type (Ca v 3.1−Ca v 3.3) components [176,179]. Thus, these channel subtypes are involved in nociception more than in any other physiologic process [180]. Interestingly, from of MVIIA, a ω-conotoxin purified from Conus magus venom, was developed Prialt TM as drug for the treatment of neuropathic pain [181]. ...
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Chapter
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