Role of M4-receptor cholinergic signaling in direct pathway striatal projection neurons during dopamine depletion
Por:
Avilés-Rosas V.H., Rendón-Ochoa E.A., Hernández-Flores T., Flores-León M., Arias C., Galarraga E., Bargas J.
Publicada:
1 ene 2024
Resumen:
Direct pathway striatal projection neurons (dSPNs) are characterized by the expression of dopamine (DA) class 1 receptors (D1R), as well as cholinergic muscarinic M1 and M4 receptors (M1R, M4R). D1R enhances neuronal firing through phosphorylation of voltage-gate calcium channels (CaV1 Ca2+ channels) activating Gs proteins and protein kinase A (PKA). Concurrently, PKA suppresses phosphatase PP-1 through DARPP-32, thus extending this facilitatory modulation. M1R also influences Ca2+ channels in SPNs through Gq proteins and protein kinase C. However, the signaling mechanisms of M4R in dSPNs are less understood. Two pathways are attributed to M4R: an inhibitory one through Gi/o proteins, and a facilitatory one via the cyclin Cdk5. Our study reveals that a previously observed facilitatory modulation via CaV1 Ca2+ channels is linked to the Cdk5 pathway in dSPNs. This result could be significant in treating parkinsonism. Therefore, we questioned whether this effect persists post DA-depletion in experimental parkinsonism. Our findings indicate that in such conditions, M4R activation leads to a decrease in Ca2+ current and an increased M4R protein level, contrasting with the control response. Nevertheless, parkinsonian and control actions are inhibited by the Cdk5 inhibitor roscovitine, suggesting Cdk5's role in both conditions. Cdk5 may activate PP-1 via PKA inhibition in DA depletion. Indeed, we found that inhibiting PP-1 restores control M4R actions, implying that PP-1 is overly active via M4Rs in DA-depleted condition. These insights contribute to understanding how DA-depletion alters modulatory signaling in striatal neurons. Additional working hypotheses are discussed. © 2024 Wiley Periodicals LLC.
Filiaciones:
Avilés-Rosas V.H.:
Instituto de Fisiología Celular, División de Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Rendón-Ochoa E.A.:
Laboratorio de Psicofarmacología, Unidad de Investigación Interdisciplinaria y de Ciencias de la Salud y Educación, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Estado de México, Tlalnepantla, Mexico
Hernández-Flores T.:
Instituto de Fisiología Celular, División de Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Flores-León M.:
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Facultad de Ciencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Arias C.:
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Galarraga E.:
Instituto de Fisiología Celular, División de Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Bargas J.:
Instituto de Fisiología Celular, División de Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
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