Selection of alternative G-mediated signaling pathways at the dopamine D2 receptor by protein kinase C

Abstract

Evidence indicates that a single membrane receptor subtype may be responsible for the generation of multiple intracellular signals, but mechanisms allowing for the selection of a specific effector pathway have not yet been documented. In neurons and other cells, the stimulation of dopamine D2 receptors produces, via G-protein activation, a spectrum of intracellular responses including inhibition of adenylyl cyclase activity, modulation of K+ currents, and potentiation of Ca(2+)-evoked arachidonic acid (AA) release. In this study, we report that, in Chinese hamster ovary cells, stimulation of protein kinase C (PKC) directs the preferential coupling of transfected D2 receptors from inhibition of adenylyl cyclase to potentiation of AA release, two responses mediated by Gi. The switch between these two signaling systems is accompanied by marked changes in their GTP sensitivities, indicating that it may result from the phosphorylation of component(s) of the receptor-Gi-protein complex. Brain PKC activity is enhanced by neurotransmitters and by neuronal depolarization. Thus, the ability of this protein kinase to remodel signaling pathways at the D2 receptor may regulate these Gi-mediated responses in an activity- dependent manner, and represent a novel form of synaptic plasticity.

Chronic Lithium Chloride Administration to Unanesthetized Rats Attenuates Brain Dopamine D2-Like Receptor-Initiated Signaling Via Arachidonic Acid

“…Thus, the blocking by lithium of k* responses to quinpirole may be due to reduced expression of the cPLA 2 coupled to D 2 receptors (Vial and Piomelli, 1995). Lithium also has been reported to reduce brain levels of the inhibitory Ga protein subunitsFGai 1 and Gai 2 Fthat couple D 2 -like receptors to PLA 2 or PLC (Carli et al, 1994;Di Marzo et al, 1993;Sidhu and Niznik, 2000;Winitz et al, 1994), and to reduce GTP binding to these subunits (Colin et al, 1991;Jakobsen and Wiborg, 1998;Li et al, 1991;Wang and Friedman, 1999). These effects also may contribute to its ability to block quinpirole k* responses.…”

Subcellular Compartmentalization of Activation and Desensitization of Responses Mediated by NK2 Neurokinin Receptors

“…It is now also well established that stimulation of one defined receptor isotype may trigger several response pathways, depending for instance on the agonist (22), on the cell type (21, 23), on the dose or duration of agonist application (24,25), or on sequential interaction with intracellular effectors (26). Although several experimental approaches have been developed to better understand, in a dynamic manner, the relationships between the receptors, their ligands, and their effectors (27)(28)(29)(30)(31), new tools are still needed to improve detection sensitivity, temporal resolution, and to allow investigation on intact cells.…”

Loss of Protein Kinase C‐αβ in Brain of Heroin Addicts and Morphine‐Dependent Rats

“….p < 0.05 (one-sample t test) . tion of guanine nucleotide binding G; proteins and catalytic unit of AC) (Takada et al ., 1985 ;Olianas and Onali, 1986;Yoshimasa et al ., 1987;Bushfield et al ., 1990), which eventually results in enhancement of AC activity (Sibley et al ., 1986;Yoshimasa et al ., 1987) or potentiation of other cellular responses associated with G;-coupled receptors (Di Marzo et al ., 1993) . Moreover, PKA and PKC have been shown to regulate in opposite directions the process of desensitization of activated K + currents induced by sustained stimulation of /j-opioid receptors in Xenopus oocytes (Chen and Yu, 1994) ; these results not only link further the opioid receptors with PKC but also indicate a possible cross talk between PKA and PKC systems in a well-defined opioid system .…”