RT Journal Article
SR Electronic
T1 Interaction of MDIMP with the voltage-gated calcium channels
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.120.119982
DO 10.1124/mol.120.119982
A1 Juan A.M. De La Rosa
A1 Maricela GarcÍa-Castañeda
A1 Takuya Nishigaki
A1 Juan Carlos Gómora
A1 Teresa Mancilla-Percino
A1 Guillermo Ávila
YR 2020
UL http://molpharm.aspetjournals.org/content/early/2020/06/25/mol.120.119982.abstract
AB Amino acid-derived isoindolines are synthetic compounds that were created with the idea of investigating their biological actions. The amino acid moiety was included on the grounds that it may help to avoid toxic effects. Recently, the isoindoline MDIMP was shown to inhibit both cardiac excitation-contraction coupling and voltage-dependent calcium channels (VDCCs). Here, we revealed that MDIMP binds preferentially to low voltage-activated (LVA) channels. Using a holding potential of -90 mV, the following IC50 values were found (in µM): >1000 (CaV2.3), 957 (CaV1.3), 656 (CaV1.2), 219 (CaV3.2), and 132 (CaV3.1). Moreover, the isoindoline also promoted both accelerated inactivation kinetics of HVA Ca2+ channels and a modest upregulation of CaV1.3 and CaV2.3. Additional data indicate that while MDIMP binds to the closed state of the channels, it has more preference for the inactivated one. Concerning CaV3.1, the compound did not alter the shape of the instantaneous I-V curve and substituting one or two residues in the selectivity filter drastically increased the IC50 value, suggesting that MDIMP binds to the extracellular side of the pore. However, an outward current failed in removing the inhibition, which implies an alternative mechanism may be involved. The enantiomer D-MDIMP, on the other hand, was synthesized and evaluated, but it did not improve the affinity to LVA channels. Implications of these findings are discussed in terms of the possible underlying mechanisms and pharmacological relevance.SIGNIFICANCE STATEMENT We have studied the regulation of VGCCs by MDIMP, which disrupts excitation-contraction coupling in cardiac myocytes. The latter effect is more potent in atrial than ventricular myocytes, and this could be explained by our results showing that MDIMP preferentially blocks low voltage-activated (LVA) channels. Our data also provide mechanistic insights about the blockade and suggest that MDIMP is a promising member of the family of Ca2+ channel blockers, with possible application to the inhibition of subthreshold membrane depolarizations.