Biology subjects

de la Rosa Vazquez, J.

Publications and source records attributed to de la Rosa Vazquez, J..

2 recordsLinked to original sources

bioRxiv2025

Inhibition of CaV1.4 channels by CaV3 channel antagonists ML218 and Z944

Among the three classes of voltage-gated Ca2+ channels (Cav1, Cav2, Cav3), Cav3 T-type channels are drug targets for disorders including epilepsy and pain. Antagonists such as Z944 and ML218 are highly selective for Cav3 compared to the Cav1.2 L-type channel but whether they have additional activity on other Cav1 subtypes is unknown. Here, we investigated the effects of Z944 and ML218 on the Cav1.4 channel which regulates neurotransmitter release from retinal photoreceptors. In HEK293T cells transfected with Cav1.4 and the auxiliary {beta}2x13 and 2{delta}-4 subunits, Z944 and ML218 inhibited Ca2+ currents with IC50 values of [~]30 {micro}M and 2 {micro}M, respectively. Structure-based modeling combined with functional studies revealed the importance of a cluster of methionine residues, particularly M1004, within the DHP binding site for the effects of ML218. Compared to mutation of a conserved threonine (T1007) that is required for DHP sensitivity of Cav1 channels, mutation of M1004 had a 10-fold greater impact in diminishing the potency of ML218. Cav1.2 was significantly less sensitive to ML218 inhibition (IC50[~] 37 {micro}M) than Cav1.4, which could not be attributed to a valine in place of M1004 in Cav1.2. We conclude that ML218 and Z944 are dual Cav1/Cav3 modulators of CaV1.4 and should be used with caution when dissecting the contributions of CaV3 channels in tissues where Cav1.4 is expressed.

biophysics↗

bioRxiv2023

A non-conducting role of the Cav1.4 Ca2+ channel drives homeostatic plasticity at the cone photoreceptor synapse

In congenital stationary night blindness type 2 (CSNB2)--a disorder involving the Cav1.4 (L-type) Ca2+ channel--visual impairment is mild considering that Cav1.4 mediates synaptic release from rod and cone photoreceptors. Here, we addressed this conundrum using a Cav1.4 knockout (KO) mouse and a knock-in (G369i KI) mouse expressing a non-conducting Cav1.4. Surprisingly, Cav3 (T-type) Ca2+ currents were detected in cones of G369i KI mice and Cav1.4 KO mice but not in cones of wild-type mouse, ground squirrel, and macaque retina. Whereas Cav1.4 KO mice are blind, G369i KI mice exhibit normal photopic (i.e., cone-mediated) visual behavior. Cone synapses, which fail to form in Cav1.4 KO mice, are present, albeit enlarged, and with some errors in postsynaptic wiring in G369i KI mice. While Cav1.4 KO mice lack evidence of cone synaptic responses, electrophysiological recordings in G369i KI mice revealed nominal transmission from cones to horizontal cells and bipolar cells. In CSNB2, we propose that Cav3 channels maintain cone synaptic output provided that the nonconducting role of Cav1.4 in cone synaptogenesis remains intact. Our findings reveal an unexpected form of homeostatic plasticity that relies on a non-canonical role of an ion channel.

neuroscience↗