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Dopamine-DARPP32 Feedback onto cAMP Pathway
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Dopamine-DARPP32 Feedback
onto cAMP Pathway

DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) is an essential modulator of dopamine signaling via cAMP, protein kinase A (PKA) and protein phosphatase-1 (PP-1) within medium spiny neurons (MSN) of the neostriatum. DARPP-32 is at the nexus of dopaminergic and glutamatergic signaling. Drugs of abuse typically enhance dopaminergic neurotransmission in dorsal and ventral striatum.

Neurotransmitters such as glutamate, serotonin and adenosine can modulate the effects of dopamine at the level of DARPP-32 phosphorylation. The activity of DARPP-32 is regulated at multiple phosphorylation sites. Dopamine binding to D1 GPCR receptors activates adenylyl cyclase through G-protein alpha(olf) (Golfalpha) subunits leading to the elevation of cAMP levels and activation of protein kinase A (PKA). Dopamine binding to D2 GPCR receptors lowers cAMP levels by inhibiting adenylyl cyclase through G-protein alpha(i) (Gαi) subunits. PKA and/or protein kinase G (PKG) phosphorylate DARPP-32 at Thr-34 and convert DARPP-32 into a potent inhibitor of the multifunctional Ser/Thr protein phosphatase-1, catalytic subunit (PP1c). PKA is inhibited by DARPP-32 that is phosphorylated at Thr-75. Cdk5 is a primary kinase responsible for phosphorylation of Thr-75 on DARPP-32.

Glutamate regulates the action of DARPP-32 and balances the dopaminergic input signals via a complex interplay of at least five temporally important ionotropic (NMDA/AMPA), and metabotropic glutamate (mGlu) receptors signaling pathways. Three pathways driven by NMDA and AMPA receptors involve: nitric oxide (NO)/cGMP/protein kinase G (PKG) (Thr-34up); calcium/calcineurin (Thr-34down); and calcium/PP-2A (Thr-75down); and two pathways driven by mGlu isotype receptors; phospholipase C (PLC)/ERK signaling (Thr-34up) and PLC/CK1/Cdk5 signaling (Thr-75up) modulate DARPP-32. Two of these pathways: PP-2B and PLC/CK1/Cdk5 are antagonistic to dopamine D1 receptor DARPP-32 signaling. DARPP-32 is dephosphorylated at Thr-34 by calcium activation of the protein phosphatase-2B (PP-2B) (calcineurin). Glutamate acting through N-methyl-D-aspartate (NMDA) receptors promotes elevation of intracellular calcium and activation of calcineurin. Group I mGlu-1 receptors stimulate phospholipase C (PLC)/CK1/Cdk5. Casein kinase I inhibits the dephosphorylation of Thr-34 by calcineurin.

References:

  1. Gould, T.D. and Manji, H.K. (2005) DARPP-32: A molecular switch at the nexus of reward pathway plasticity. Natl. Acad. Sci. U.S.A. 102, 253-254. Comment in: Proc. Natl. Acad. Sci. U.S.A. 102, 491-496.
  2. Nairn, A.C. et. al. (2004) The role of DARPP-32 in the actions of drugs of abuse. Neuropharmacology. 47, 14-23.
  3. Neve, K.A. et. al. (2004) Dopamine receptor signaling. J. Recept. Signal. Transduct. Res. 24, 165-205.
  4. Nishi, A. et. al.(2005) Glutamate regulation of DARPP-32 phosphorylation in neostriatal neurons involves activation of multiple signaling cascades. Proc. Natl. Acad. Sci. U.S.A. 102, 1199-1204.
  5. Valjent, E. et. al. (2005) Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proc. Natl. Acad. Sci. U.S.A. 102, 491-496. Comment in: Proc. Natl. Acad. Sci. U.S.A. 102, 253-254.

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