دورية أكاديمية
أعرض في EDS

Inhibitory Mechanism of the Isoflavone Derivative Genistein in the Human Ca V 3.3 Channel.

التفاصيل البيبلوغرافية
العنوان: Inhibitory Mechanism of the Isoflavone Derivative Genistein in the Human Ca V 3.3 Channel.
المؤلفون: Rangel-Galván M; School of Chemical Sciences, Meritorious Autonomous University of Puebla (BUAP), University City, Puebla 72570, Mexico., Rangel A; Coordinación Académica Región Altiplano, Universidad Autónoma de San Luis Potosí, San Luis Potosí 78700, México., Romero-Méndez C; Departamento de Fisiología y Biofísica, Facultad de Medicina Universidad Autónoma de San Luis Potosí, San Luis Potosí 78210, México., Dávila EM; School of Chemical Sciences, Meritorious Autonomous University of Puebla (BUAP), University City, Puebla 72570, Mexico., Castro ME; Chemistry Center, Science Institute, Meritorious Autonomous University of Puebla (BUAP), University City, Puebla 72570, Mexico., Caballero NA; School of Biological Sciences, Meritorious Autonomous University of Puebla (BUAP), University City, Puebla 72570, Mexico., Meléndez Bustamante FJ; School of Chemical Sciences, Meritorious Autonomous University of Puebla (BUAP), University City, Puebla 72570, Mexico., Sanchez-Gaytan BL; Chemistry Center, Science Institute, Meritorious Autonomous University of Puebla (BUAP), University City, Puebla 72570, Mexico., Meza U; Departamento de Fisiología y Biofísica, Facultad de Medicina Universidad Autónoma de San Luis Potosí, San Luis Potosí 78210, México., Perez-Aguilar JM; School of Chemical Sciences, Meritorious Autonomous University of Puebla (BUAP), University City, Puebla 72570, Mexico.
المصدر: ACS chemical neuroscience [ACS Chem Neurosci] 2021 Feb 17; Vol. 12 (4), pp. 651-659. Date of Electronic Publication: 2021 Jan 28.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101525337 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1948-7193 (Electronic) Linking ISSN: 19487193 NLM ISO Abbreviation: ACS Chem Neurosci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Chemical Society
مواضيع طبية MeSH: Calcium Channels, T-Type* , Depressive Disorder, Major* , Isoflavones*, Cryoelectron Microscopy ; Genistein/pharmacology ; Humans
مستخلص: Regulation of cellular excitability and oscillatory behavior of resting membrane potential in nerve cells are largely mediated by the low-voltage activated T-type calcium channels. This calcium channel family is constituted by three isoforms, namely, Ca V 3.1, Ca V 3.2, and Ca V 3.3, that are largely distributed in the nervous system and other parts of the body. Dysfunction of T-type calcium channels is associated with a wide range of pathophysiologies including epilepsy, neuropathic pain, cardiac problems, and major depressive disorders. Due to their pharmacological relevance, finding molecular agents able to modulate the channel's function may provide therapeutic means to ameliorate their related disorders. Here we used electrophysiological experiments to show that genistein, a canonical tyrosine kinase inhibitor, reduces the activity of the human Ca V 3.3 channel in a concentration-dependent manner. The inhibitory effect of genistein is independent of tyrosine kinase modulation and does not affect the voltage-dependent gating of the channel. Subsequently, we used computational methods to identify plausible molecular poses for the interaction of genistein and the Ca V 3.3 channel. Starting from different molecular poses, we carried out all-atom molecular dynamics (MD) simulations to identify the interacting determinants for the Ca V 3.3/genistein complex formation. Our extensive (microsecond-length) simulations suggest specific binding interactions that seem to stabilize the protein/inhibitor complex. Furthermore, our results from the unbiased MD simulations are in good agreement with the recently solved cryoelectron microscopy structure of the Ca V 3.1/Z944 complex in terms of both the location of the ligand binding site and the role of several equivalent amino acid residues. Proposed interacting complex loci were subsequently tested and corroborated by electrophysiological experiments using another naturally occurring isoflavone derivative, daidzein. Thus, by using a combination of in vitro and in silico techniques, we have identified interacting determinants relevant to the Ca V 3.3/genistein complex formation and propose that genistein directly blocks the function of the human Ca V 3.3 channel as a result of such interaction. Specifically, we proposed that a combination of polar interactions involving the three hydroxyl groups of genistein and an aromatic interaction with the fused rings are the main binding interactions in the complex formation. Our results pave the way for the rational development of improved and novel low-voltage activated T-type calcium channel inhibitors.
فهرسة مساهمة: Keywords: LVA channels; MD simulations; T-type calcium channels; channel blockers; channel inhibition; isoflavone derivative
المشرفين على المادة: 0 (Calcium Channels, T-Type)
0 (Isoflavones)
DH2M523P0H (Genistein)
تواريخ الأحداث: Date Created: 20210128 Date Completed: 20210618 Latest Revision: 20210618
رمز التحديث: 20221213
DOI: 10.1021/acschemneuro.0c00684
PMID: 33507062
قاعدة البيانات: MEDLINE
الوصف
تدمد:1948-7193
DOI:10.1021/acschemneuro.0c00684