The L‐type calcium channel CaV1.3: A potential target for cancer therapy

Figures

• 

  FIGURE 1. Schematic structure of CaV1.3. (A) CaV1.3 subunit topology map. The CaV1.3 α1 subunit contains four homologous structural domains (I–IV), each with six transmembrane fragments (S1–S6). S1–S4 constitute the voltage‐sensing domains (VSD) and S5 and S6 constitute the pore domain (PD). (B) Structure of human CaV1.3 (Protein Data Bank: 7UHG) shown from the membrane. (C) Observation of the α1 subunit from the extracellular view shows a domain exchange structure.

• 

  FIGURE 2. Expression of CaV1.3 in several common cancers and the role of CCBs in cancer cells (Created in BioRender.com).

• 

  FIGURE 3. Schematic representation of the regulation of CaV1.3 in cancers. In prostate cancer cells (LNCaP cells), androgen‐stimulated Ca2+ influx involves CaV1.3 calcium channels, which are also AR‐dependent. 57 L‐type channel Cav1.3‐dependent Ca2+ influx is essential for AR‐mediated gene expression. 57 In endometrial and breast cancers, oestrogen mediates CaV1.3 calcium influx via GPR30, activates p‐ERK1/2 expression, and enhances CaV1.3 expression. 69 , 78 In EC, oestrogen‐induced extracellular Ca2+ influx promotes EC progression by regulating lysosomal activity and mitochondrial ROS. 74 In breast cancer, integrin inside‐out signalling promotes Ca2+ entry at filopodia tips, via CaV1.3, and subsequent filopodia stability. 79 In colon cancer, α1D protein regulates the migration and invasion of HCT116 cells and its intracellular Ca2+ concentration by a mechanism that did not depend on its plasma membrane canonical function but that involved plasma membrane NCX1/3 exchangers and ER Ca2+ release. 84 CACNA1D may also be regulated by some non‐coding RNAs (e.g. TRF‐Val‐CAC‐016 and miR‐371a‐3p). DHT, Dihydrotestosterone; E2: 17β‐estradiol; AR, Androgen receptor; ER, Endoplasmic reticulum;…

• 

  FIGURE 4. The structural formula of the LTCC blockers, and PYT's mechanism for CaV1.3 preferences. (A) Common blockers of L‐type calcium channels (nifedipine, verapamil, and diltiazem, which are used in the treatment of hypertension) and compound 8 (which may be selective for CaV1.3). (B) Targeted mutagenesis based on homology modelling of the CaV1.3 and CaV1.2 channels revealed that a single amino acid residue within the DHP‐binding pocket (M1078) resulted in a higher selectivity of PYT for CaV1.3 than for CaV1.2. This graph is quoted from Cooper G et al. 131