Dopamine-DARPP32 Feedback in cAMP Signaling


Pathway Description

Dopamine and glutamine are two primary neurotransmitters in the brain. Dopamine is a derivative of the amino acid tyrosine. It is the predominant catecholamine neurotransmitter in the mammalian brain where it controls functions such as locomotor activity, cognition, emotion, positive reinforcement, food intake and endocrine regulation. Neurons in the midbrain release dopamine, which modulates cAMP production by activating dopamine receptors. On the basis of their molecular structure and pharmacological properties, these receptors are divided into the D1 class (DRD1 and DRD5) and D2 class (DRD2, DRD3, and DRD4). These receptors work via Gαi and Gαs to modulate synthesis of cAMP, resulting in the stimulation and increase of intracellular Ca2+ and leading to activation of downstream signaling.Binding of dopamine to its D1 class of receptors is stimulated by psychostimulants such as cocaine and amphetamine, whereas antipsychotics inhibit the action of the D2 class of receptors. Major downstream targets include IRKC channels, VGKC channels, L-Type CaCn, NMDAR/GRIN, AMPAR/GRIA. Upon activation by dopamine and psychostimulants, increased cAMP levels activates PKA which leads to activation of the transcription factors ATF1, CREM and CREB. Inhibition of these transcription factors by PP1 phosphatase leads to the disruption of communication in the dopamine system and ultimately results in a variety of neurological, psychiatric disorders, including schizophrenia, Tourette syndrome, obsessive-compulsive disorder, Parkinson's disease and Huntington's disease. Therefore, effective control over the dopamine-activated cAMP/PKA signaling pathway is important.

Dopamine-induced gene activation is partially controlled by a protein called Dopamine and cAMP Regulated Phosphoprotein-32 (DARPP32), forming a feedback loop on the cAMP/PKA signaling cascade. The dopamine-DARPP-32 feedback mechanism is necessary to maintain the physiological state of the cell and is controlled by signal transduction mechanisms which regulate the balance between protein kinase and protein phosphatase activities. Activation of PKA or PKG stimulates DARPP32 phosphorylation at Thr34 and thereby converts DARPP32 into a potent inhibitor of PP1 phosphatase. DARPP32 is also phosphorylated at Thr75 by CDK5, and this converts DARPP32 into an inhibitor of PKA. Thus, DARPP32 has the unique property of being a dual-function protein, acting either as an inhibitor of PP1 or of PKA . By virtue of this ability, DARPP32 is critically involved in regulating electrophysiological, transcriptional, and behavioral responses to physiological and pharmacological stimuli, including antidepressants, neuroleptics and illicit drugs.