The gβγ Dimer as a Novel Source of Selectivity in G-Protein Signaling: GGL-ing AT CONVENTION

Dopaminergic transmission between the substantia nigra and striatum. (A) Normally, neurons originating from the substantia nigra and terminating in the striatum release dopamine to propagate signals to cholinergic interneurons and GABAergic neurons, leading to inhibition of output from the GABAergic neurons. (B) In Parkinson’s disease, these nigrostriatal dopaminergic neurons are progressively lost (gray), causing an imbalance in the normal control of posture and fine motor movement owing to increased GABAergic output from this circuit. l-DOPA, the immediate precursor of dopamine, is used in anti-Parkinson’s pharmacotherapy to restore dopamine receptor-mediated inhibition of this neuronal circuit. Adding an RGS9-2 inhibitor as an adjuvant to l-DOPA should potentiate dopamine receptor signaling by blunting negative regulation via RGS domain–mediated GAP activity.