Further evidence for the role of the α2
δ subunit of voltage dependent calcium channels in models of neuropathic pain

Ifenprodil is a selective blocker of NMDA receptors that are heterodimers composed of GluN1/GluN2B subunits. This pharmacological profile has been extensively used to test the role of GluN2B-containing NMDA receptors in learning and memory formation. However, ifenprodil has also been reported to have actions at a number of other receptors, including high voltage-activated calcium channels. Here we show that, in the basolateral amygdala, ifenprodil dose dependently blocks excitatory transmission to principal neurons by a presynaptic mechanism. This action of ifenprodil has an IC50 of ∼10 μM and is fully occluded by the P/Q type calcium channel blocker ω-agatoxin. We conclude that ifenprodil reduces synaptic transmission in the basolateral amygdala by partially blocking P-type voltage-dependent calcium channels.

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Identification of the target of gabapentinoid action in neuropathic pain

10.1093/med/9780198834359.003.0070 ◽

2018 ◽

Author(s):

Turo J. Nurmikko

Keyword(s):

Neuropathic Pain ◽

Scientific Community ◽

Oral Absorption ◽

Molecular Target ◽

Wild Type ◽

Seminal Paper ◽

Voltage Gated ◽

Voltage Dependent ◽

Voltage Dependent Calcium Channels

The landmark paper discussed in this chapter is ‘Identification of the α‎2-δ‎-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin’, published by Field et al. in 2006. In this seminal paper, Field et al. demonstrated that the anti-allodynic effect of pregabalin is related to its binding to the α‎2δ‎-1 subunit of the voltage-gated calcium channel. In transgenic mice lacking this subunit, pregabalin had no effect on allodynia induced by sciatic nerve ligation, whereas, in wild-type mice, there was a substantial anti-allodynic response. This discovery was well received by the scientific community and was considered to conclusively establish the mechanism of action of pregabalin, which has remarkably similar properties to gabapentin but with increased potency and oral absorption. This exciting result acted as an impetus for further studies on the role of the subunit in the development and maintenance of neuropathic pain.

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On the Role of Voltage-Dependent Calcium Channels in Calcium Signaling of AstrocytesIn Situ

Journal of Neuroscience ◽

10.1523/jneurosci.18-12-04637.1998 ◽

1998 ◽

Vol 18 (12) ◽

pp. 4637-4645 ◽

Cited By ~ 121

Author(s):

Giorgio Carmignoto ◽

Lucia Pasti ◽

Tullio Pozzan

Keyword(s):

Calcium Channels ◽

Calcium Signaling ◽

Voltage Dependent ◽

Voltage Dependent Calcium Channels

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Role of L-type and N-type Voltage-dependent Calcium Channels (VDCCs) on Spontaneous Acetylcholine Release at the Mammalian Neuromuscular Junction

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1998.tb10995.x ◽

1998 ◽

Vol 841 (1 MYASTHENIA GR) ◽

pp. 636-645 ◽

Cited By ~ 6

Author(s):

ADRIANA LOSAVIO ◽

SALOMON MUCHNIK

Keyword(s):

Neuromuscular Junction ◽

Calcium Channels ◽

Acetylcholine Release ◽

Voltage Dependent ◽

Voltage Dependent Calcium Channels

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N-Type Voltage-Dependent Calcium Channels Mediate the Nicotinic Enhancement of GABA Release in Chick Brain

Journal of Neurophysiology ◽

10.1152/jn.1999.81.2.447 ◽

1999 ◽

Vol 81 (2) ◽

pp. 447-454 ◽

Cited By ~ 24

Author(s):

Trevor L. Tredway ◽

Jian-Zhong Guo ◽

Vincent A. Chiappinelli

Keyword(s):

Calcium Channels ◽

Channel Blocker ◽

Brain Slices ◽

Gaba Release ◽

Channel Blockers ◽

Chick Brain ◽

Voltage Dependent ◽

Voltage Dependent Calcium Channels ◽

Whole Cell Recordings

N-type voltage-dependent calcium channels mediate the nicotinic enhancement of GABA release in chick brain. The role of voltage-dependent calcium channels (VDCCs) in the nicotinic acetylcholine receptor (nAChR)-mediated enhancement of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) was investigated in chick brain slices. Whole cell recordings of neurons in the lateral spiriform (SpL) and ventral lateral geniculate (LGNv) nuclei showed that cadmium chloride (CdCl2) blocked the carbachol-induced increase of spontaneous GABAergic IPSCs, indicating that VDCCs might be involved. To conclusively show a role for VDCCs, the presynaptic effect of carbachol on SpL and LGNv neurons was examined in the presence of selective blockers of VDCC subtypes. ω-Conotoxin GVIA, a selective antagonist of N-type channels, significantly reduced the nAChR-mediated enhancement of γ-aminobutyric acid (GABA) release in the SpL by 78% compared with control responses. Nifedipine, an L-type channel blocker, and ω-Agatoxin-TK, a P/Q-type channel blocker, did not inhibit the enhancement of GABAergic IPSCs. In the LGNv, ω-Conotoxin GVIA also significantly reduced the nAChR-mediated enhancement of GABA release by 71% from control values. Although ω-Agatoxin-TK did not block the nicotinic enhancement, L-type channel blockers showed complex effects on the nAChR-mediated enhancement. These results indicate that the nAChR-mediated enhancement of spontaneous GABAergic IPSCs requires activation of N-type channels in both the SpL and LGNv.

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