Constitutive activity of dopamine receptor type 1 (D1R) increases Ca<sub>V</sub>2.2 currents in PFC neurons

Alterations in dopamine receptor type 1 (D1R) density are associated with cognitive deficits of aging and schizophrenia. In the prefrontal cortex (PFC), D1R plays a critical role in the regulation of working memory, which is impaired in these cognitive deficit states, but the cellular events trigger...

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Autores principales: McCarthy, Clara Inés, Chou Freed, Cambria, Rodríguez, Silvia Susana, Yaneff, Agustín, Davio, Carlos, Raingo, Jesica
Formato: Articulo
Lenguaje:Inglés
Publicado: 2020
Materias:
Ciencias Exactas
Biología
Neurons
Prefrontal cortex
Dopamine receptor
Cellular Physiology
Membrane Transport
Molecular Pharmacology
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/124770
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-124770
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Exactas
Biología
Neurons
Prefrontal cortex
Dopamine receptor
Cellular Physiology
Membrane Transport
Molecular Pharmacology
spellingShingle Ciencias Exactas
Biología
Neurons
Prefrontal cortex
Dopamine receptor
Cellular Physiology
Membrane Transport
Molecular Pharmacology
McCarthy, Clara Inés
Chou Freed, Cambria
Rodríguez, Silvia Susana
Yaneff, Agustín
Davio, Carlos
Raingo, Jesica
Constitutive activity of dopamine receptor type 1 (D1R) increases Ca<sub>V</sub>2.2 currents in PFC neurons
topic_facet Ciencias Exactas
Biología
Neurons
Prefrontal cortex
Dopamine receptor
Cellular Physiology
Membrane Transport
Molecular Pharmacology
description Alterations in dopamine receptor type 1 (D1R) density are associated with cognitive deficits of aging and schizophrenia. In the prefrontal cortex (PFC), D1R plays a critical role in the regulation of working memory, which is impaired in these cognitive deficit states, but the cellular events triggered by changes in D1R expression remain unknown. A previous report demonstrated that interaction between voltage-gated calcium channel type 2.2 (Ca<sub>V</sub>2.2) and D1R stimulates Ca<sub>V</sub>2.2 postsynaptic surface location in medial PFC pyramidal neurons. Here, we show that in addition to the occurrence of the physical receptor-channel interaction, constitutive D1R activity mediates up-regulation of functional Ca<sub>V</sub>2.2 surface density. We performed patch-clamp experiments on transfected HEK293T cells and wild-type C57BL/6 mouse brain slices, as well as imaging experiments and cAMP measurements. We found that D1R coexpression led to ∼60% increase in Ca<sub>V</sub>2.2 currents in HEK293T cells. This effect was occluded by preincubation with a D1/D5R inverse agonist, chlorpromazine, and by replacing D1R with a D1R mutant lacking constitutive activity. Moreover, D1R-induced increase in Ca<sub>V</sub>2.2 currents required basally active Gs protein, as well as D1R-Ca<sub>V</sub>2.2 interaction. In mice, intraperitoneal administration of chlorpromazine reduced native Ca<sub>V</sub> currents' sensitivity to ω-conotoxin-GVIA and their size by ∼49% in layer V/VI pyramidal neurons from medial PFC, indicating a selective effect on Ca<sub>V</sub>2.2. Additionally, we found that reducing D1/D5R constitutive activity correlates with a decrease in the agonist-induced D1/D5R inhibitory effect on native Ca<sub>V</sub> currents. Our results could be interpreted as a stimulatory effect of D1R constitutive activity on the number of Ca<sub>V</sub>2.2 channels available for dopamine-mediated modulation. Our results contribute to the understanding of the physiological role of D1R constitutive activity and may explain the noncanonical postsynaptic distribution of functional Ca<sub>V</sub>2.2 in PFC neurons.
format Articulo
Articulo
author McCarthy, Clara Inés
Chou Freed, Cambria
Rodríguez, Silvia Susana
Yaneff, Agustín
Davio, Carlos
Raingo, Jesica
author_facet McCarthy, Clara Inés
Chou Freed, Cambria
Rodríguez, Silvia Susana
Yaneff, Agustín
Davio, Carlos
Raingo, Jesica
author_sort McCarthy, Clara Inés
title Constitutive activity of dopamine receptor type 1 (D1R) increases Ca<sub>V</sub>2.2 currents in PFC neurons
title_short Constitutive activity of dopamine receptor type 1 (D1R) increases Ca<sub>V</sub>2.2 currents in PFC neurons
title_full Constitutive activity of dopamine receptor type 1 (D1R) increases Ca<sub>V</sub>2.2 currents in PFC neurons
title_fullStr Constitutive activity of dopamine receptor type 1 (D1R) increases Ca<sub>V</sub>2.2 currents in PFC neurons
title_full_unstemmed Constitutive activity of dopamine receptor type 1 (D1R) increases Ca<sub>V</sub>2.2 currents in PFC neurons
title_sort constitutive activity of dopamine receptor type 1 (d1r) increases ca<sub>v</sub>2.2 currents in pfc neurons
publishDate 2020
url http://sedici.unlp.edu.ar/handle/10915/124770
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