Glutamic acid regulation of Dopamine D1A receptor
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 .
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 ,  and/or protein Phosphatase 1, regulatory subunit 1A
(IPP-1) at Thr 35 . Thr 35-phosphorylated
IPP-1 and Thr
34-phosphorylated DARPP-32 inhibit Protein phosphatase1
catalytic subunit (PP1-cat) , .
PKA and PP1-cat regulate the
phosphorylation state and activity of many physiological effectors, including
neurotransmitter receptors that regulate excitability of medium spiny neurons.
and/or PKA activation
may lead to stimulation of Gamma-aminobutyric acid (GABA) A receptor
(GABA-A receptor)  and/or cAMP responsive
element binding protein 1 (CREB1) .
It is shown, that Glutamic acid may
regulate Dopamine D1A receptor signaling via multiple
receptors, e.g., Glutamate receptor, metabotropic 1 (mGluR1)
, Glutamate receptor ionotropic N-methyl
D-aspartate (NMDA) and Glutamate receptor ionotrophic AMPA
(AMPA) . All three receptors raise
cytosolic Ca2+ 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 . NMDA and
AMPA activate Ca2+ transport
from extracellular region to cytosol . Cytosol
Ca2+ activates Protein phosphatase 3
(Calcineurin) , /
Calcineurin dephosphorylates inhibitory
autophosphorylation sites of Casein Kinase I epsilon
resulting in its activation . Casein Kinase I
epsilon activates cyclin-dependent kinase 5 regulatory subunit 1
(CDK5R1(p35))/ Cyclin-dependent kinase 5
(CDK5) . CDK5,
in turn, stimulates the phosphorylation of DARPP-32 at
Thr-75 ,  and IPP-1
at Ser 67 .
DARPP-32 phosphorylated at Thr 75 inhibits
phosphorylated at Ser 67
does not inhibit PP1-cat .
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 . It leads to inhibit of PP-1cat.
In addition, Calcineurin may
dephosphorylate DARPP-32 at
Thr 34 , . It leads to activation of
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) , . PP2A directly dephosphorylates
DARPP-32 at Thr 75 ,  and IPP-1 at
Ser 67 . The latter leads to activation of
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