Structural basis for human Cav1.2 inhibition by multiple drugs and the neurotoxin calciseptine

Cell. 2023 Nov 22;186(24):5363-5374.e16. doi: 10.1016/j.cell.2023.10.007. Epub 2023 Nov 15.


Cav1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Cav1.2, both in its apo form and in complex with several drugs, as well as the peptide neurotoxin calciseptine. Most structures, apo or bound to calciseptine, amlodipine, or a combination of amiodarone and sofosbuvir, exhibit a consistent inactivated conformation with a sealed gate, three up voltage-sensing domains (VSDs), and a down VSDII. Calciseptine sits on the shoulder of the pore domain, away from the permeation path. In contrast, when pinaverium bromide, an antispasmodic drug, is inserted into a cavity reminiscent of the IFM-binding site in Nav channels, a series of structural changes occur, including upward movement of VSDII coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5III merges with S5III to become a single helix, resulting in a widened but still non-conductive intracellular gate.

Keywords: Ca(v)1.2; L-type calcium channels; LTCC; amiodarone; amlodipine; calciseptine; channel inactivation; pinaverium bromide; sofosbuvir; voltage-gated calcium channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium Channels, L-Type* / chemistry
  • Calcium Channels, L-Type* / metabolism
  • Cryoelectron Microscopy
  • Elapid Venoms*
  • Humans
  • Neurotoxins
  • Protein Domains


  • CACNA1C protein, human
  • calciseptine
  • Calcium Channels, L-Type
  • Elapid Venoms
  • Neurotoxins