Signal transduction in Parkinson's disease: modulation of neurotransmission, symptomatology, and therapy

Abstract Signal transduction downstream of G protein–coupled receptors is an important modulator of neurotransmission. These processes are fundamental for a number of neuronal functions and underlie several motor, cognitive, and psychiatric phenotypes. Parkinson's disease severely affects signal transduction pathways due to neurodegeneration per se as well as through molecular and circuit rearrangements. Great attention has been given to functionality of dopamine receptors, as their signaling pathways are directly affected by neuronal loss in the substantia nigra pars compacta and explain motor dysfunctions in disease. In addition, alterations in those cellular processes are at the basis of the most severe side effects of l -Dopa therapy—i.e., dyskinesias. Additional neurotransmitter systems play important roles in physiological brain functions and are affected in Parkinson's disease, such as those utilizing metabotropic glutamate receptors, serotonin receptors, and acetylcholine muscarinic receptors. These have been targeted not only for alternative therapies but also to modulate important nonmotor symptoms. Importantly, emerging evidence indicates that the signal transduction of dopamine and nondopamine receptors is also hampered by protein products of the genetic causes of familial Parkinson's disease, linking etiology and symptomatology. Future work will elucidate the precise mechanisms that might explain the molecular causes of disease, not only in familial patients but also in idiopathic Parkinson's disease.