Pathway Map DetailsNeurophysiological process_Glutamate regulation of Dopamine D1A receptor signaling
Object list (links open in MetaCore):
Adenylate cyclase type V, DARPP-32, NMDA receptor, IPP-1, cAMP, Ca('2+) endoplasmic reticulum lumen, AMPA receptor, Calmodulin, GABA-A receptor beta-1 subunit, IP3 receptor, DAG, PLC-beta2, IP3, PP2A structural, PKA-cat (cAMP-dependent), PP2A regulatory, Description:
Glutamic acid regulation of Dopamine D1A receptor signaling Glutamic acid is the major excitatory neurotransmitter in the brain. The excitation of medium spiny neurons is regulated by a balance of glutamatergic inputs from corticostriatal and thalamostriatal pathways and dopaminergic inputs from the nigrostriatal pathway [1]. Dopamine D1A receptor signaling cascade, that contains a specific Guanine nucleotide binding protein GNAS complex locus ( G-protein alpha-s )/ Adenylate cyclase type V/ Cyclic adenosine monophosphate ( cAMP ), activates cAMP-dependent protein kinase ( PKA ). PKA phosphorylates DARPP-32 at Thr 34 [2], [3] and/or protein Phosphatase 1, regulatory subunit 1A ( IPP-1 ) at Thr 35 [4]. Thr 35-phosphorylated IPP-1 and Thr 34-phosphorylated DARPP-32 inhibit Protein phosphatase1 catalytic subunit ( PP1-cat ) [4], [3]. PKA and PP1-cat regulate the phosphorylation state and activity of many physiological effectors, including neurotransmitter receptors that regulate excitability of medium spiny neurons. PP-1 inhibition and/or PKA activation may lead to stimulation of Gamma-aminobutyric acid (GABA) A receptor ( GABA-A receptor ) [5] and/or cAMP responsive element binding protein 1 ( CREB1 ) [6]. It is shown, that Glutamic acid may regulate Dopamine D1A receptor signaling via multiple receptors, e.g., Glutamate receptor, metabotropic 1 ( mGluR1) [6] , Glutamate receptor ionotropic N-methyl D-aspartate ( NMDA ) and Glutamate receptor ionotrophic AMPA ( AMPA ) [7]. All three receptors raise cytosolic Ca 2+ level. mGluR1 activates a cascade that composes of G-protein alpha-q/ Phospholipase C, beta 1 ( PLC beta 1 )/ Inositol 1,4,5-trisphosphate ( IP3 ). This cascade activates Ca2+ transport from endoplasmic reticulum to cytosol [8]. NMDA and AMPA activate Ca2+ transport from extracellular region to cytosol [7]. Cytosol Ca 2+ activates Protein phosphatase 3 ( Calcineurin ) [7], [8]/ Calcineurin dephosphorylates inhibitory autophosphorylation sites of Casein Kinase I epsilon resulting in its activation [8]. Casein Kinase I epsilon activates cyclin-dependent kinase 5 regulatory subunit 1 ( CDK5R1(p35 ))/ Cyclin-dependent kinase 5 ( CDK5 ) [4]. CDK5, in turn, stimulates the phosphorylation of DARPP-32 at Thr-75 [2], [9] and IPP-1 at Ser 67 [10]. DARPP-32 phosphorylated at Thr 75 inhibits PKA. IPP-1 phosphorylated at Ser 67 does not inhibit PP1-cat [10]. This leads to activation of PP-1cat and synergistically reduces phosphorylation of its various common substrates. Ser 67-phosphorylated IPP-1 may be dephosphorylated by Calcineurin [10]. It leads to inhibit of PP-1cat. In addition, Calcineurin may dephosphorylate DARPP-32 at Thr 34 [11], [7]. It leads to activation of PP-1cat. Moreover, Glutamic acid via NMDA and AMPA raise intracellular Ca2+. This stimulates Protein phosphatase 2 ( PP2A ), possibly via Calmodulin/ Striatin calmodulin binding proteins ( Striatin and SG2NA ) [12], [7]. PP2A directly dephosphorylates DARPP-32 at Thr 75 [11], [7] and IPP-1 at Ser 67 [10]. The latter leads to activation of PP-1 cat. References:
|
