Cav2.3 R-type calcium channels: from its discovery to pathogenic de novo CACNA1E variants: a historical perspective

So-called pharmacoresistant (R-type) voltage-gated Ca(2+) channels are structurally only partially characterized. Most of them are encoded by the CACNA1E gene and are expressed as different Ca(v)2.3 splice variants (variant Ca(v)2.3a to Ca(v)2.3e or f) as the ion conducting subunit. So far, no inherited disease is known for the CACNA1E gene but recently spontaneous mutations leading to early death were identified, which will be brought into focus. In addition, a short historical overview may highlight the development to understand that upregulation during aging, easier activation by spontaneous mutations or lack of bioavailable inorganic cations (Zn(2+) and Cu(2+)) may lead to similar pathologies caused by cellular overexcitation.