cAMP-regulated phosphoproteins DARPP-32, ARPP16/19, and RCS modulate striatal signal transduction through protein kinases and phosphatases.

Decades of research led by Paul Greengard identified protein phosphorylation as a ubiquitous and vital post-translational modification involved in many neuronal signaling pathways. In particular, his discovery that second messenger-regulated protein phosphorylation plays a central role in the propagation and transduction of signals in the nervous system has been essential in understanding the molecular mechanisms of neuronal communication. The establishment of dopamine (DA) as an essential neurotransmitter in the central nervous system, combined with observations that DA activates G-protein-coupled receptors to control the production of cyclic adenosine monophosphate (cAMP) in postsynaptic neurons, has provided fundamental insight into the regulation of neurotransmission. Notably, DA signaling in the striatum is involved in many neurological functions such as control of locomotion, reward, addiction, and learning, among others. This review focuses on the history, characterization, and function of cAMP-mediated regulation of serine/threonine protein phosphatases and their role in DA-mediated signaling in striatal neurons. Several small, heat- and acid-stable proteins, including DARPP-32, RCS, and ARPP-16/19, were discovered by the Greengard laboratory to be regulated by DA- and cAMP signaling, and found to undergo a complex but coordinated sequence of phosphorylation and dephosphorylation events. These studies have contributed significantly to the establishment of protein phosphorylation as a ubiquitous and vital process in signal propagation in neurons, paradigm shifting discoveries at the time. Understanding DA-mediated signaling in the context of signal propagation has led to numerous insights into human conditions and the development of treatments and therapies.