Here, we show that Cacna2d1 overexpression potentiates presynaptic and postsynaptic NMDAR activity of spinal dorsal horn neurons to cause pain hypersensitivity.
We examined the genetic variants of THBS1 and CACNA2D1 in two independent cohorts of patients affected by IGE/GGE recruited through the Genetic Commission of the Italian League Against Epilepsy (LICE) and the EuroEPINOMICS-CoGIE Consortium.
Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (<i>KCTD7</i>, <i>ARHGEF15</i>, <i>CACNA2D1, GRIN2A</i> and <i>ARHGEF4</i>), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development.
The proximity to the WS region of the gene encoding the L-type voltage-gated calcium channel alpha 2/delta-subunit (CACNL2A) on 7q11.23-q21.1, previously shown to be closely linked to some forms of MH susceptibility, prompted us to investigate whether this gene is deleted in WS.
CACNA2 encodes the alpha(2)/delta subunit of the human voltage-gated calcium channels and is located in the candidate region of malignant hyperthermia susceptibility type 3 (MHS3).
Previously, we identified the calcium voltage-gated channel auxiliary subunit alpha2delta 1 gene (<i>Cacna2d1</i>) as a modulator of IOP and demonstrated that pregabalin, a drug with high affinity and selectivity for CACNA2D1, lowered IOP in a dose-dependent manner.
Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype.
Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found.
Inhibiting α2δ-1 with gabapentin, uncoupling the α2δ-1-NMDAR interaction with an α2δ-1 C terminus-interfering peptide, or genetically ablating Cacna2d1 had no effect on basal NMDAR currents but strikingly abolished oxygen-glucose deprivation-induced NMDAR hyperactivity in hippocampal CA1 neurons.
The sequence analysis provides the basis for comprehensive mutation screening of CACNA2 for putative MHS3 individuals and patients with other channelopathies.
The inherited-familial forms are not frequent in IVF; however mutations were identified in the genes KCNJ8, DPP6, SCN5A, SCN3B, CACNA1C, CACNB2, and CACNA2D1.
These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.