Dopamine receptors · Lobeworks/17

Dopamine receptors are the five G-protein-coupled receptors through which dopamine acts, grouped in two families: the D1-like receptors (D1 and D5), which raise cyclic AMP inside the cell, and the D2-like receptors (D2, D3 and D4), which lower it, so the same dopamine pulse pushes one neuron one way and its neighbour t

Dopamine receptors. Dopamine receptors are the five G-protein-coupled receptors through which dopamine acts, grouped in two families: the D1-like receptors (D1 and D5), which raise cyclic AMP inside the cell, and the D2-like receptors (D2, D3 and D4), which lower it, so the same dopamine pulse pushes one neuron one way and its neighbour the other.

All five are metabotropic: none opens a channel directly. D1-like receptors couple to the G proteins Gs and Golf and switch adenylyl cyclase on; D2-like receptors couple to Gi and Go and switch it off, and the change in cyclic AMP and protein kinase A then retunes channels, receptors and plasticity over hundreds of milliseconds to minutes. In the striatum, the input stage of the basal ganglia, the two families sit on different cells: neurons of the direct pathway, which releases movement, carry D1; neurons of the indirect pathway, which holds it back, carry D2. Dopamine therefore helps both ways at once, encouraging the go route and quieting the stop route. D2 receptors on dopamine terminals also act as autoreceptors that throttle further release.

D1 excites, D2 inhibits is a first approximation. The receptors change a second messenger, and what that does to firing depends on the cell, the channels it carries, the dose of dopamine and the state of the circuit; the sign is a tendency, never a law.

Every antipsychotic on the market blocks D2 receptors, and the clinical potency of the older drugs tracks how strongly they bind D2-like receptors. In a classic imaging study, response became likely once about 65 % of striatal D2 receptors were occupied, and parkinsonian side effects once occupancy passed about 78 %: blocking too much takes away the push dopamine gives to movement.

The blockade is reached within hours, while the clinical effect builds over weeks, one sign that the receptor is the first step of a slower adaptation, not the whole mechanism (see receptor regulation).

Kebabian and Calne named the two families in 1979, from the observation that some dopamine responses raised cyclic AMP and others did not.

The receptor decides the sign, not the transmitter.

Dopamine carries one message; whether it reads as go or stop depends on which family the listening cell expresses.

Questions: How do D1 and D2 receptors split the direct and indirect pathways of the basal ganglia? In the striatum the two families sit on different projection neurons. Direct-pathway neurons, whose output releases movement, carry D1 receptors; indirect-pathway neurons, whose output holds movement back, carry D2. A burst of dopamine therefore strengthens the go route and weakens the stop route at the same time, both pushing toward action. Losing dopamine in Parkinson's disease does the reverse on both sides, which is why movement becomes slow and scarce, and why blocking D2 receptors with antipsychotics can produce parkinsonian stiffness. Why is *D1 excites, D2 inhibits* only a first approximation? Neither receptor opens a channel: D1-like receptors raise cyclic AMP through Gs or Golf, D2-like receptors lower it through Gi or Go, and the second messenger then retunes potassium and calcium channels, glutamate receptors and plasticity in whatever way that cell is built. So D1 tends to make a striatal neuron more responsive to its excitatory input and D2 less, which is where the rule of thumb comes from, but the actual effect on firing depends on the cell type, the membrane state, the dopamine concentration and the circuit around it. The sign is a tendency of the second messenger, not a fixed property of the receptor like the chloride current of a GABA-A receptor. Why does a drug acting on a receptor lose part of its effect with repeated use? Because cells adjust their receptors to the signal they keep receiving. A drug that keeps activating a receptor drives its desensitisation and removal, so the same dose produces less, which is tolerance, and stopping it leaves too few receptors for the normal signal, felt as withdrawal. A drug that keeps blocking one does the reverse: long blockade of D2 dopamine receptors by older antipsychotics raises their number in the striatum, the leading explanation of the late movement disorder tardive dyskinesia.