Abstract
In the principal neurons of striatum (medium spiny neurons, MSNs), cAMP pathway is primarily activated through the stimulation of dopamine D1 and adenosine A2A receptors, these receptors being mainly expressed in striatonigral and striatopallidal MSNs, respectively. Since cAMP signaling pathway could be altered in various physiological and pathological circumstances, including drug addiction and Parkinson’s disease, it is of crucial importance to identify the molecular components involved in the activation of this pathway. In MSNs, cAMP pathway activation is not dependent on the classical Gs GTP-binding protein but requires a specific G protein subunit heterotrimer containing Gαolf/β2/γ7 in particular association with adenylyl cyclase type 5. This assembly forms an authentic functional signaling unit since loss of one of its members leads to defects of cAMP pathway activation in response to D1 or A2A receptor stimulation, inducing dramatic impairments of behavioral responses dependent on these receptors. Interestingly, D1 receptor (D1R)-dependent cAMP signaling is modulated by the neuronal levels of Gαolf, indicating that Gαolf represents the rate-limiting step in this signaling cascade and could constitute a critical element for regulation of D1R responses. In both Parkinsonian patients and several animal models of Parkinson’s disease, the lesion of dopamine neurons produces a prolonged elevation of Gαolf levels. This observation gives an explanation for the cAMP pathway hypersensitivity to D1R stimulation, occurring despite an unaltered D1R density. In conclusion, alterations in the highly specialized assembly of Gαolf/β2/γ7 subunits can happen in pathological conditions, such as Parkinson’s disease, and it could have important functional consequences in relation to changes in D1R signaling in the striatum.
Highlights
Dopamine, probably the best characterized neurotransmitter involved in slow synaptic neurotransmission, plays a prominent role in a variety of brain functions, including motor control, motivation, short-term memory, and reward (Schultz, 1998)
Different approaches using in situ hybridization, immunocytochemistry, and transgenic mice indicate that D1 receptor (D1R) in the striatum is highly expressed in a subpopulation of GABAergic medium spiny neurons (MSNs) projecting to the substantia nigra and entopeduncular nucleus and containing substance P and dynorphin as co-neurotransmitters (Gerfen et al, 1990; Le Moine and Bloch, 1995; Yung et al, 1995; Drago et al, 1998b; Gong et al, 2003; Lee et al, 2006; Bertran-Gonzalez et al, 2008)
Reduction in D1R in mice heterozygous for null mutation of D1R gene did not alter significantly this response. These results show that the levels of Gαolf protein, but not D1R, constitute a limiting factor determining the amplitude of cAMP pathway response upon D1R activation in the striatal neurons
Summary
Probably the best characterized neurotransmitter involved in slow synaptic neurotransmission, plays a prominent role in a variety of brain functions, including motor control, motivation, short-term memory, and reward (Schultz, 1998). Five genes encoding dopamine receptors have been cloned in mammals (see Sibley and Monsma, 1992 for review). D2 receptors are essentially present in the MSNs projecting to the globus pallidus and containing enkephalins (indirect pathway of basal ganglia). These neurons express abundantly the adenosine A2A receptors that are able to stimulate production of intracellular cAMP (Schiffmann et al, 2007). The population of MSNS coexpressing both D1R and D2 receptor, is low in the dorsal striatum and core of nucleus accumbens (about 5%) but is slightly higher in the shell of nucleus accumbens (17%; Bertran-Gonzalez et al, 2008; Hasbi et al, 2009; Matamales et al, 2009)
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