Unveiling β Subunit-Dependent Gating Defects in CaV2.1 Channelopathies: Investigation of a de novo CACNA1A Variant by Kunpeng Ma & Haiyan Chen & Li Chen & Shuainan Zhao & Huafang Zou & Dongfang Zou & Qi Zeng & Dezhi Cao & Jianyuan Sun & Lin Li & Xuefeng Shen instant download

Unveiling β Subunit-Dependent Gating Defects in CaV2.1 Channelopathies: Investigation of a de novo CACNA1A Variant by Kunpeng Ma & Haiyan Chen & Li Chen & Shuainan Zhao & Huafang Zou & Dongfang Zou & Qi Zeng & Dezhi Cao & Jianyuan Sun & Lin Li & Xuefeng Shen instant download

Neuroscience Bulletin,Dear Editor,Clinically distinct phenotypes have been molecularly stratifed based on the functional consequences: loss-ofThe CaV2.1 channel, also known as the P/Q-type Ca2+function (LOF) variants predominantly underlie episodic channel, is a particular type of voltage-gated Ca2+ chanataxia type 2 (EA2), whereas gain-of-function (GOF) varinel primarily expressed on the presynaptic membrane in ants are classically linked to familial hemiplegic migraine the brain [1]. It serves as an essential part of the precisely type 1 [6]. However, emerging evidence indicates that a suborchestrated neurotransmitter release machinery, playing a set of missense variants can lead to overlapping symptomacrucial role in the regulation of synaptic transmission [2, tology (OS), characterized by a combination of ataxia and/3]. Structurally, the CaV2.1 channel complex comprises a or migraine, as well as additional clinical symptoms (e.g., principal α1 subunit (encoded by CACNA1A) that forms the developmental epileptic encephalopathy (DEE), stroke, ion-conducting pore, accompanied by auxiliary β and α2δ autism, and respiratory failure) [6–8]. Notably, these severe subunits [4]. The α1 subunit features a canonical architecphenotypes challenge the simplistic GOF/LOF dichotomy ture of four homologous domains (DI–DIV), each containin the CaV2.1 channelopathies [9]. Intriguingly, some OSing six transmembrane segments (S1–S6) responsible for related variants exhibit dual functional efects, displaying voltage sensing (S1–S4) and ion selectivity and permeation both GOF and LOF alterations in activities of the CaV2.1 (S5 and S6) [1]. Pathogenic variants in CACNA1A manifest channel [9]. Despite these fndings, the precise molecular as heterogeneous neurological disorders collectively termed mechanisms underlying OS remain poorly understood.