Chlorpromazine, an Inverse Agonist of D1R-Like, Differentially Targets Voltage-Gated Calcium Channel (Ca V ) Subtypes in mPFC Neurons.

Autor: McCarthy CI; Electrophysiology Laboratory of the Multidisciplinary Institute of Cell Biology (Argentine Research Council CONICET, Scientific Research Commission of the Buenos Aires Province and National University of La Plata), La Plata, Buenos Aires, Argentina., Mustafá ER; Electrophysiology Laboratory of the Multidisciplinary Institute of Cell Biology (Argentine Research Council CONICET, Scientific Research Commission of the Buenos Aires Province and National University of La Plata), La Plata, Buenos Aires, Argentina., Cornejo MP; Neurophysiology Laboratory of the Multidisciplinary Institute of Cell Biology (Argentine Research Council CONICET, Scientific Research Commission of the Buenos Aires Province and National University of La Plata), La Plata, Buenos Aires, Argentina., Yaneff A; Instituto de Investigaciones Farmacológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina., Rodríguez SS; Electrophysiology Laboratory of the Multidisciplinary Institute of Cell Biology (Argentine Research Council CONICET, Scientific Research Commission of the Buenos Aires Province and National University of La Plata), La Plata, Buenos Aires, Argentina., Perello M; Neurophysiology Laboratory of the Multidisciplinary Institute of Cell Biology (Argentine Research Council CONICET, Scientific Research Commission of the Buenos Aires Province and National University of La Plata), La Plata, Buenos Aires, Argentina.; Department of Surgical Sciences, Functional Pharmacology and Neuroscience, University of Uppsala, Uppsala, Sweden., Raingo J; Electrophysiology Laboratory of the Multidisciplinary Institute of Cell Biology (Argentine Research Council CONICET, Scientific Research Commission of the Buenos Aires Province and National University of La Plata), La Plata, Buenos Aires, Argentina. jraingo@gmail.com.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2023 May; Vol. 60 (5), pp. 2644-2660. Date of Electronic Publication: 2023 Jan 25.
DOI: 10.1007/s12035-023-03221-1
Abstrakt: The dopamine receptor type 1 (D1R) and the dopamine receptor type 5 (D5R), which are often grouped as D1R-like due to their sequence and signaling similarities, exhibit high levels of constitutive activity. The molecular basis for this agonist-independent activation has been well characterized through biochemical and mutagenesis in vitro studies. In this regard, it was reported that many antipsychotic drugs act as inverse agonists of D1R-like constitutive activity. On the other hand, D1R is highly expressed in the medial prefrontal cortex (mPFC), a brain area with important functions such as working memory. Here, we studied the impact of D1R-like constitutive activity and chlorpromazine (CPZ), an antipsychotic drug and D1R-like inverse agonist, on various neuronal Ca V conductances, and we explored its effect on calcium-dependent neuronal functions in the mouse medial mPFC. Using ex vivo brain slices containing the mPFC and transfected HEK293T cells, we found that CPZ reduces Ca V 2.2 currents by occluding D1R-like constitutive activity, in agreement with a mechanism previously reported by our lab, whereas CPZ directly inhibits Ca V 1 currents in a D1R-like activity independent manner. In contrast, CPZ and D1R constitutive activity did not affect Ca V 2.1, Ca V 2.3, or Ca V 3 currents. Finally, we found that CPZ reduces excitatory postsynaptic responses in mPFC neurons. Our results contribute to understanding CPZ molecular targets in neurons and describe a novel physiological consequence of CPZ non-canonical action as a D1R-like inverse agonist in the mouse brain.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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