Role of M4 -receptor cholinergic signaling in direct pathway striatal projection neurons during dopamine depletion.

Direct pathway striatal projection neurons (dSPNs) are characterized by the expression of dopamine (DA) class 1 receptors (D1 R), as well as cholinergic muscarinic M1 and M4 receptors (M1 R, M4 R). D1 R enhances neuronal firing through phosphorylation of voltage-gate calcium channels (CaV 1 Ca2+ channels) activating Gs proteins and protein kinase A (PKA). Concurrently, PKA suppresses phosphatase PP-1 through DARPP-32, thus extending this facilitatory modulation. M1 R also influences Ca2+ channels in SPNs through Gq proteins and protein kinase C. However, the signaling mechanisms of M4 R in dSPNs are less understood. Two pathways are attributed to M4 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 CaV 1 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, M4 R activation leads to a decrease in Ca2+ current and an increased M4 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 M4 R actions, implying that PP-1 is overly active via M4 Rs in DA-depleted condition. These insights contribute to understanding how DA-depletion alters modulatory signaling in striatal neurons. Additional working hypotheses are discussed.

Milium coloide: reporte de un caso y revisión de la literatura / Colloid milium: a case report and review of the literature

Resumen El milium coloide (MC) es un trastorno de depósito cutáneo poco común, asociado a cambios degenerativos secundarios a la radiación ultravioleta, que provoca degeneración de las fibras elásticas en la dermis. Tiene dos formas de presentación definidas como juvenil y del adulto. Es más común en hombres que realizan oficios al aire libre. Clínicamente se caracteriza por numerosas y pequeñas pápulas de distintos colores (amarillo, ámbar, café) o translúcidas, que suelen agruparse y se localizan en zonas fotoexpuestas. El diagnóstico se confirma mediante el estudio histopatológico y pudiera requerir tinciones especiales para diferenciar la mucina y el amiloide. Para su tratamiento se han empleado técnicas como dermoabrasión mecánica, láseres, terapia fotodinámica, entre otros.

Abstract Colloid milium is a rare skin deposition disorder associated with degenerative changes secondary to ultraviolet radiation, which causes degeneration of elastic fibers in the dermis. It has two forms of presentation defined as juvenile and adult. It is more common in men who work outdoors. Clinically it is characterized by numerous small yellow, brown, amber or translucent papules that are usually grouped together, located over photo-exposed areas. The diagnosis is confirmed by histopathological study and may require special stains to differentiate mucin and amyloid. Techniques such as mechanical dermabrasion, lasers, photodynamic therapy, among others, have been used for its treatment.