RESUMO
The M(3) muscarinic acetylcholine receptor (mAChR) expressed in HEK-293 cells couples to G(q) and G(12) proteins and stimulates phospholipase C (PLC) and phospholipase D (PLD) in a pertussis toxin-insensitive manner. To determine the type of G protein mediating M(3) mAChR-PLD coupling in comparison to M(3) mAChR-PLC coupling, we expressed various Galpha proteins and regulators of the G protein signaling (RGS), which act as GTPase-activating proteins for G(q)- or G(12)-type G proteins. PLD stimulation by the M(3) mAChR was enhanced by the overexpression of Galpha(12) and Galpha(13), whereas the overexpression of Galpha(q) strongly increased PLC activity without affecting PLD activity. Expression of the RGS homology domain of Lsc, which acts specifically on Galpha(12) and Galpha(13), blunted the M(3) mAChR-induced PLD stimulation without affecting PLC stimulation. On the other hand, overexpression of RGS4, which acts on Galpha(q)- but not Galpha(12)-type G proteins, suppressed the M(3) mAChR-induced PLC stimulation without altering PLD stimulation. We conclude that the M(3) mAChR in HEK-293 cells apparently signals to PLD via G(12)- but not G(q)-type G proteins and that G protein subtype-selective RGS proteins can be used as powerful tools to dissect the pertussis toxin-resistant G proteins and their role in receptor-effector coupling.
Assuntos
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Fosfolipase D/metabolismo , Receptores Muscarínicos/metabolismo , Carbacol/farmacologia , Resistência a Medicamentos , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP , Humanos , Agonistas Muscarínicos/farmacologia , Toxina Pertussis , Proteínas RGS/metabolismo , Receptor Muscarínico M3 , Transdução de Sinais , Fosfolipases Tipo C/metabolismo , Fatores de Virulência de Bordetella/farmacologiaRESUMO
Presbyophrenia is characterized by memory impairment, disorientation, confabulation, hypomanic features, and a preserved social facade. These occur in the absence of prior history of alcoholism or affective illness. We present three cases with presbyophrenia and suggest that the syndrome is a recognizable subtype of dementia, possibly related to disruption of aminergic pathways in frontal and subcortical structures.
