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Effect of dopamine on intracellular signaling pathways. Stimulation of receptors by agonists can change enzyme activities as well as gene expression. Five subtypes of dopamine receptor have been identified. The D1 and D5 receptors are coupled to adenylyl cyclase (AC) via a stimulatory G protein (G_S). The D2 receptor inhibits cyclase activity via coupling to an inhibitory G protein (G_i). Activation of D3 and D4 receptors also inhibits cAMP production. Adenylyl cyclase catalyzes the conversion of ATP into cAMP, which in turn causes dissociation of the regulatory and catalytic subunits of protein kinase A. The activated catalytic subunit catalyzes conversion of protein substrates into phosphoproteins. This is turn can lead to a short-term response within the cell or activate transcription factors (TF) which enter the nucleus and alter gene expression. Long-term gene responses can be initiated by the action of constitutively expressed TFs either directly on DNA or via a mechanism involving transcription of an immediate-early gene (IEG) and cytoplasmic production of its protein. This protein can then act on DNA via an adaptor protein 1 (AP-1)-binding site . TF, constitutively expressed transcription factors, such as a cAMP-response element (CRE), IEG, immediate-early genes, such as c-fos,c-junand knox.

(SEE COLOR INSERT FOLLOWING PAGE 204) Dendrograms illustrating relative expression levels of representative transcripts for several single-cell expression profile paradigms. (A) A comparison of expression profiles from normal control CA1 pyramidal neurons and NFT-bearing CA1 neurons in AD. (B) Color-coded matrix plots illustrating relative expression levels for individual glutamate receptor transcripts in CA1 and CA3 neurons. Single asterisk indicates a significant increase in expression of AMPA receptors GRIA1 and GRIA2 in CA3 neurons as compared to CA1 neurons. Double asterisks denote significant increases in relative expression levels in CA1 pyramidal neurons as compared to CA3 pyramidal neurons for kainate receptor KA1 (GRIK4) and NMDA receptors NMDAR1 (GRIN1) and NMDAR2B (GRIN2B). (C) Dendrogram and histogram depicting individual GABA A receptor and dopamine receptor mRNA expression levels in CA1 and CA3 pyramidal neurons microaspirated from human hippocampus. Color matrix plot illustrates expression levels for six GABA A receptors, five dopamine receptors, and the dopamine transporter in CA1 and CA3 pyramidal neurons. Double asterisk indicates genes that have significantly greater relative expression levels in CA1 neurons as compared to CA3 neurons including GABA A receptors (GABRA1, GABRA2), and the D1, D2, and D5 dopamine receptors (DRD1, DRD2, and DRD5)
Key: 3Rtau, three-repeat tau; 4Rtau, four-repeat tau; ACT, alpha-1-antichymotrypsin precursor; ACTB, beta-actin; APOE, apolipoprotein E; APP, amyloid-beta precursor protein; arc, activity regulated cytoskeletal-associated protein; CAMKII, calcium/calmodulin-dependent protein kinase II, alpha; CDK2, cyclin-dependent kinase 2; cdk5, cyclin-dependent kinase 5; cdk5R1, cyclin-dependent kinase 5, regulatory subunit 1 (p35); c-fos, cellular oncogene fos; c-jun, jun oncogene; CREB, cAMP responsive element binding protein; CTSD, cathepsin D; DAT, dopamine transporter; DRD1, dopamine receptor D1; DRD2, dopamine receptor D2; DRD3, dopamine receptor D3; DRD4, dopamine receptor D4; DRD5, dopamine receptor D5; ERK1, extracellular signal-regulated kinase 1 (p44); ERK2, extracellular signal-regulated kinase (p42); FAK, focal adhesion kinase; GABRA1, GABA A receptor, alpha 1; GABRA2, GABA A receptor, alpha 2; GABRA3, GABA A receptor, alpha 3; GABRA4, GABA A receptor, alpha 4; GABRA5, GABA A receptor, alpha 5; GABRA6, GABA A receptor, alpha 6; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GRIA1, AMPA1; GRIA2, AMPA2; GRIA3, AMPA3; GRIA4, AMPA4; GRIK1, kainate 1(GluR5); GRIK2, kainate 2(GluR6), GRIK3, kainate 3(GluR7); GRIN1, N-methyl D-aspartate 1(NMDAR1); GRIN2A, NMDAR2A; GRIN2B, NMDAR2B; GRIN2C, NMDAR2C; GRIN2D, NMDAR2D; GRX, glutaredoxin; GSK-3B, glycogen synthase kinase-3 beta; HSPG, heparan sulfate proteoglycan; MAP1b; microtubule-associated protein 1b; MAP2, microtubule-associated protein 2; NF-H, neurofilament heavy subunit; NF-L, neurofilament light subunit; NF-M, neurofilament medium subunit; PP1A, protein phosphatase 1 catalytic subunit, alpha isoform; PP1G, protein phosphatase 1, catalytic subunit, gamma isoform; PP2AB, protein phosphatase 2, regulatory subunit A, beta isoform; PP2AC, protein phosphatase 2, catalytic subunit, alpha isoform; PSEN1, presenilin 1; PSEN2, presenilin 2; SNCA, alpha synuclein; SNCB, beta synuclein; SYN1, synapsin 1; SYP, synaptophysin; SYT, synaptotagmin; TUBB, beta-tubulin.