Fig 1 D1-like vs D2-like signalling hover or focus a part · space: pause D1 cAMP up · D2 cAMP down
dopamine-releasing terminal
AC + − βγ Gαs/olf GDP GTP βγ Gαi/o GDP GTP
C C R
OH OH NH2 dopamine C8 H 11 NO 2 vesicle D1 receptor D2 receptor membrane adenylyl cyclase ATP → cAMP cAMP PKA D1-like receptor Gαs/olf · stimulates AC · cAMP ↑ D2-like receptor Gαi/o · inhibits AC · cAMP ↓ dopamine (not to scale)
GDP on α: GDP (resting)
GTP on α: GTP (active)
generic D2 antagonist + stimulates AC (D1 path) − inhibits AC (D2 path) arrow = where α·GTP travels brightness = how strong (qualitative) medium spiny neuron (postsynaptic) · schematic patch Schematic, not to scale. Flat cross-section of a dopamine synapse onto a striatal medium spiny neuron, simplified to D1 and D2 only. D1 and D2 are drawn on one membrane to compare them; in striatum they sit mostly on different neurons. Qualitative levels only.
Dopamine level low medium high D2 antagonist (generic) Pause motion
Hover or focus a labelled part for a one-line explanation.
What the figure shows, and how sure we are
Receptor families and coupling (well established). D1-like receptors (D1, D5) couple to Gs and activate adenylyl cyclase; D2-like receptors (D2, D3, D4) inhibit adenylyl cyclase (Missale et al. 1998, Physiol Rev ; Beaulieu & Gainetdinov 2011, Pharmacol Rev , which also covers signalling beyond cAMP). In striatal medium spiny neurons the D1 receptor works through Gαolf (with Gβ2γ7 and adenylyl cyclase type 5), and D1-type signalling raises cAMP and PKA activity (Hervé 2011, Front Neuroanat , open access).G-protein cycle (well established). The activated receptor catalyses GDP release and GTP binding on Gα; Gα·GTP and Gβγ separate and act on effectors including adenylyl cyclases; signalling ends when Gα's own GTPase turns GTP into GDP and the heterotrimer re-forms, a step sped up by RGS proteins (McCudden et al. 2005, Cell Mol Life Sci , open access; Oldham & Hamm 2008, Nat Rev Mol Cell Biol ). For Gi proteins, subunit rearrangement without full dissociation has been reported (Bünemann et al. 2003, cited in Hervé 2011), so the separate-and-rejoin drawing is the classic textbook model, not the last word.PKA. cAMP-dependent protein kinase is a tetramer of two regulatory and two catalytic subunits; cAMP binding to R is believed to liberate active kinase, though in anchored (AKAP) complexes the catalytic subunit may stay close (“Intrinsic disorder within an AKAP-protein kinase A complex guides local substrate phosphorylation”, eLife 2013 , open access).Striatal cell types. D1 receptors are mainly on striatonigral (direct pathway) MSNs and D2 receptors on striatopallidal (indirect pathway) MSNs (Gerfen et al. 1990, Science ; Surmeier et al. 2007, Trends Neurosci ). Co-expression is low in dorsal striatum; the reference above (Hervé 2011) discusses estimates. The one-membrane drawing is a teaching device.Affinity and the three levels. The model treats D2 as high-affinity and D1 as low-affinity, so low dopamine already engages D2 while D1 needs high dopamine; bursts mainly raise D1 occupancy (Dreyer et al. 2010, J Neurosci , which cites Rice & Cragg 2008 for the affinities). The occupancy values behind the slider are illustrative and are not shown; no concentration is claimed.Terminal. VMAT2 loads dopamine into vesicles and DAT clears it from the cleft (Dopamine D1, D2, D3 receptors, VMAT2 and DAT densities in aged human brain, PLoS ONE 2012 , introduction); nigrostriatal input to the striatum is described in the Gerfen 1990 abstract.Molecule. Dopamine, 4-(2-aminoethyl)benzene-1,2-diol, C8H11NO2 (PubChem CID 681 ).
What was simplified. Only D1 and D2 are drawn; D3, D4 and D5, receptor dimers and heteromers (such as D1–D2), β-arrestin signalling, Gαq/phospholipase C coupling, βγ effectors, DARPP-32, phosphodiesterases (which break cAMP down), presynaptic D2 autoreceptors, dopamine reuptake and breakdown, and extrasynaptic volume transmission are left out. D1 and D2 are drawn on one membrane sharing one adenylyl cyclase; in the striatum they are mostly in different cells, so the shared cAMP stream is only a way to show that the two pathways push in opposite directions. Sizes, positions and timing are illustrative; protein shapes are cartoons, not structures. “Generic D2 antagonist” is a teaching toggle: it is not a named drug and says nothing about any dose.
For education only; this figure is not medical advice and says nothing about any person’s treatment or any medicine.