Dopamine D2 receptors: key regulators of dopaminergic functions

Dopamine has a central role in the regulation of a variety of brain functions, ranging from locomotion to motivated behaviors, to learning and memory. Absence or alteration of the dopaminergic control profoundly affects human physiology leading to neurological and neuropsychiatric disorders, such as Parkinson's disease and schizophrenia. Dopamine acts through the interaction with membrane receptors of the G-protein coupled receptor family. We have approached the study of D2 receptor (D2R) mediated signaling. Interestingly, two D2R isoforms are present in all vertebrates including humans, D2L and D2S, generated by alternative splicing of the same gene. Genetically engineered mice lacking both D2 isoforms show several deficits, among those, motor impairments and aberrant responses to drugs of abuse. Mice lacking only D2L show altered postsynaptic functions while preserve the control of dopamine release, which is mainly regulated by D2S. This functional difference indicates that regulation of splicing constitutes a key step in the control of D2-mediated functions.