DARPP-32

2022-04-19: reference:

DARPP-32 (dopamine- and cAMP-regulated regulated neuronal phosphoprotein) (PP1 regulatory subunit 1B (PPP1R1B)) #

• Expressed in D1-type Medium Spiny Neurons in the Striatum.

• these are my kind of “protein bars”. My life now.

  • Activated/phosphorylated by Protein Kinase A (thus when D1 is stimulated). When NMDARs are stimulated, Ca2+ influx activates PP2B, which dephosphorylates.
  • Dephosphorylated at Thr34 most potently by PP2B. PP2A also dephosphorylates most others.
  • The T34 and T75 have an interesting feedback mechanism: PKA->PP1 activates CREB->FosB->CDK5, which returns to inhibit PKA, which prevents CREB’s activation.
    • It looks like CDK5 could be the savior, but it does other naughty shit, like Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors

• When phosphorylated at Thr34 DARPP-32 is a potent inhibitor of PP1, whereas when phosphorylated at Thr75 by CDK5 it inhibits Protein Kinase A. Phosphorylation at serine residues by CK1 and CK2 modulates its intracellular localization and its sensitivity to kinases or phosphatases.

  • PP1 is normally maintaining dephosphorylization of CREB. By potently inhibiting it, it increases CREB’s duration of phosphorylation. Only DARPP-32-expressing cells exhibit the prolonged phosphorylation of CREB that is required it to exert its effects on expression.
    • I don’t exactly believe this because I feel like if CREB is there regardless, it would still be doing something. Or it’s just ready for drugs/toxins/etc.?

  • Under hyperdopaminergic conditions, the phosphorylated state of Thr75 is reduced allowing increased phosphorylation at Thr34. #

• @Signaling in Striatal Neurons The Phosphoproteins of Reward, Addiction, and Dyskinesia (Girault 2012)