Instituto de Fisiología Celular, División de Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, México.
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, Tlalnepantla, Estado de México, México.
Synapse. 2024 Mar;78(2):e22287. doi: 10.1002/syn.22287.
Direct pathway striatal projection neurons (dSPNs) are characterized by the expression of dopamine (DA) class 1 receptors (D R), as well as cholinergic muscarinic M and M receptors (M R, M R). D R enhances neuronal firing through phosphorylation of voltage-gate calcium channels (Ca 1 Ca channels) activating Gs proteins and protein kinase A (PKA). Concurrently, PKA suppresses phosphatase PP-1 through DARPP-32, thus extending this facilitatory modulation. M R also influences Ca channels in SPNs through Gq proteins and protein kinase C. However, the signaling mechanisms of M R in dSPNs are less understood. Two pathways are attributed to M R: 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 Ca 1 Ca 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, M R activation leads to a decrease in Ca current and an increased M R 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 M R actions, implying that PP-1 is overly active via M Rs in DA-depleted condition. These insights contribute to understanding how DA-depletion alters modulatory signaling in striatal neurons. Additional working hypotheses are discussed.
直接通路纹状体投射神经元（dSPNs）的特征是表达多巴胺（DA）1 类受体（DR），以及胆碱能毒蕈碱 M 和 M 受体（MR、MR）。DR 通过电压门控钙通道（Ca1Ca 通道）的磷酸化增强神经元放电，激活 Gs 蛋白和蛋白激酶 A（PKA）。同时，PKA 通过 DARPP-32 抑制磷酸酶 PP-1，从而延长这种促进性调节。MR 还通过 Gq 蛋白和蛋白激酶 C 影响 SPNs 中的 Ca 通道。然而，MR 在 dSPNs 中的信号机制了解较少。MR 有两条途径：一条是通过 Gi/o 蛋白的抑制途径，另一条是通过 cyclin Cdk5 的促进途径。我们的研究表明，先前观察到的通过 Ca1Ca 通道的促进性调节与 dSPNs 中的 Cdk5 途径有关。这一结果在治疗帕金森病方面可能具有重要意义。因此，我们质疑这种效应是否在实验性帕金森病中持续存在。我们的发现表明，在这种情况下，MR 激活导致 Ca 电流减少和 MR 蛋白水平增加，与对照反应相反。然而，帕金森病和对照作用都被 Cdk5 抑制剂罗西维林抑制，表明 Cdk5 在两种情况下都发挥作用。Cdk5 可能通过 PKA 抑制在 DA 耗竭中激活 PP-1。事实上，我们发现抑制 PP-1 恢复了对照 MR 作用，这意味着在 DA 耗竭条件下，PP-1 通过 MR 过度活跃。这些见解有助于理解 DA 耗竭如何改变纹状体神经元的调节信号。讨论了其他工作假设。
