Regulation of the Ca²⁺channel α₂δ-1 subunit expression by epidermal growth factor via the ERK/ELK-1 signaling pathway

Abstract

<jats:p> Voltage-gated Ca<jats:sup>2+</jats:sup> (Ca<jats:sub>V</jats:sub>) channels are expressed in endocrine cells where they contribute to hormone secretion. Diverse chemical messengers, including epidermal growth factor (EGF), are known to affect the expression of Ca<jats:sub>V</jats:sub> channels. Previous studies have shown that EGF increases Ca<jats:sup>2+</jats:sup> currents in GH3 pituitary cells by increasing the number of high voltage-activated (HVA) Ca<jats:sub>V</jats:sub> channels at the cell membrane, which results in enhanced prolactin (PRL) secretion. However, little is known regarding the mechanisms underlying this regulation. Here, we show that EGF actually increases the expression of the Ca<jats:sub>V</jats:sub>α<jats:sub>2</jats:sub>δ-1 subunit, a key molecular component of HVA channels. The analysis of the gene promoter encoding Ca<jats:sub>V</jats:sub>α<jats:sub>2</jats:sub>δ-1 ( CACNA2D1) revealed binding sites for transcription factors activated by the Ras/Raf/MEK/ERK signaling cascade. Chromatin immunoprecipitation and site-directed mutagenesis showed that ELK-1 is crucial for the transcriptional regulation of CACNA2D1 in response to EGF. Furthermore, we found that EGF increases the membrane expression of Ca<jats:sub>V</jats:sub>α<jats:sub>2</jats:sub>δ-1 and that ELK-1 overexpression increases HVA current density, whereas ELK-1 knockdown decreases the functional expression of the channels. Hormone release assays revealed that Ca<jats:sub>V</jats:sub>α<jats:sub>2</jats:sub>δ-1 overexpression increases PRL secretion. These results suggest a mechanism for how EGF, by activating the Ras/Raf/MEK/ERK/ELK-1 pathway, may influence the expression of HVA channels and the secretory behavior of pituitary cells. </jats:p>

Calcium channelopathies and intellectual disability: a systematic review

“…Induced pluripotent stem cells (iPSCs) and HEK293T cells for spinocerebellar ataxia [ 302 ] Endostatin, zonisamide, clozapine, roscovitine, mibefradil, iron and zinc can block Cav3.1 channel [ 179 – 185 ] Dearomatized isoprenylated acylphloroglucinol and monoterpenoid, hypatone A could rescue pathological gating properties for spinocerebellar ataxia 42 [ 186 ] Autophagic pathway in melanoma cells [ 198 ] Apoptotic pathway in [ 193 – 195 ] Ras-ERK signaling pathway [ 200 , 201 ] CACNA1H Calcium voltage-gated channel subunit alpha1 H Cav3.2 T-type None TsA-201 cell for amyotrophic lateral sclerosis [ 303 ] KYS-05090S can block Cav3.2 current [ 187 ] Apoptotic pathway in myocardial cells [ 155 ]. Autophagy pathway [ 158 ] CACNA1I Calcium Voltage-Gated Channel Subunit Alpha1 I Cav 3.3 T-type HEK293T and mouse chromaffin cells for ID and epilepsy [ 74 ] None Zinc modulates Cav3.3 channel gating [ 181 ] None CACNA2D1 Calcium voltage-gated channel auxiliary subunit alpha2delta 1 Cav1.3 L-type None MKN74 cells (human gastric cancer cell line) [ 190 ] MicroRNA-107 can inhibit expression of Cav1.3 in cancer [ 188 , 189 ] Amlodipine can block Cav1.3 in cancer [ 190 ] CXCR3/ERK1/2 signaling pathway [ 203 ] Ras/Raf/MEK/ERK signaling pathway [ 202 ] …”

Sympathetic Stimulation Upregulates the Ca2+ Channel Subunit, CaVα2δ1, via the β1 and ERK 1/2 Pathway in Neonatal Ventricular Cardiomyocytes

“…A previous study reported that EGF stimulation of GH3 pituitary cells increased Ca V α2δ1 protein levels via recruitment of the ras/MEK/ERK1/2 signaling pathway [ 34 ]. In NRVMs, sympathetic stimulation of the β 1 -adrenergic receptor is known to promote ERK1/2 phosphorylation [ 35 ].…”