• G_{α s} proteins activate one of the Adenylyl Cyclases (ADCY), which generates cyclic AMP from ATP. Cyclic AMP in turn activates another membrane-associated enzyme: protein kinase A (PKA). PKA then phosphorylates a number of other proteins in or near the membrane, including some K⁺ channels; these close when phosphorylated, leaving the membrane more labile to depolarization. In many epithelial tissues PKA activates proteins that transport the working membrane proteins of that tissue toward the apex of the cell, where they do their work. The effects of PKA on neurons are still being worked out.
• G_{α i} proteins inhibits Adenyl Cyclase and the production of cyclic AMP. These proteins also open K⁺ channels, which makes the neuron harder to depolarize.
• G_{α q/11} stimulates membrane-bound phospholipase C (PLC); activated PLC cleaves PIP₂ (a minor membrane phosphoinositol) into inositol tri-phosphate (IP3) and diacylglycerol (DAG). IP3 is water soluble and travels through the cytoplasm and activates protein kinase C (PKC), which in turn phosphorylates many other targets.

Serotonin receptors:

The 5-HT (serotonin) receptors form a family within the lineage of GPCR's (shown below) as well as one ligand gated channel - HTR3A. Molecular clock evidence suggests this family started about 800Myr ago. Some members of this family have since evolved specificity for responding to noradrenalin or dopamine. Almost all family members have been conserved within the mammal lineage since we branched from reptiles.

Dopamine receptors:

The D1 family (D1,D5) have short internal loops and long C-tails; the D2 family have long loops and short C-tails.

These physical characteristics predispose D1 family members to recruit G_s proteins, and increase cAMP; they generally decrease K⁺, and therefore increase the spontaneous activity and also the responsiveness of cells.

On the other hand D2 family receptors primarily recruit G_i proteins and increase K⁺ conductance, leading to decreased activity.

Our set of 5 distinct dopamine receptors has been conserved from the time of reptiles. Invertebrates have very distantly related dopamine receptors that don't correspond individually to our receptors.

D1 and D5 are part of the G_s branch of the HTR family (see above).

• D1 receptor is common in the striatum and NA; K_m = 2000 nM (low affinity).
• D5 receptor occurs in Hippocampus and hypothalamus; K_m = 200 nM (moderate).
• D2 receptors occur in the striatum and NA; some are auto-receptors; K_m = 400nM (moderate)
• D3 receptors occur in the NA and hypothalamus; K_m = 25 nM (strong affinity); decreases Ca++ conductance
• D4 receptors occur in the cortex; K_m = 20nM (strong affinity)

Peptides

Several G-protein receptors become active upon binding of peptides with closely paired Tyr/Phe residues at the N-terminal. These pairs occur at the N-terminal of a number of signaling peptides, including enkephalins, β-endorphin, and others. Several of these signaling peptides (e.g. β-endorphin) are derived by cutting fragments from the product of the POMC gene, expressed only in the pituitary gland, while others (dynorphins) are derived from the PDYN gene, which is expressed in caudate nucleus and pons and less in amygdala, and others (enkephalins) are derived from the PENK gene, expressed at very high levels in caudate. The receptors for these peptides are mostly G_s type, which increase cAMP. Some of these receptors (the μ-opioid receptors) are also triggered by morphine, which led to their discovery. The receptors come in three main flavors: μ,δ,κ, which have different distributions in the brain and have acquired different affinities for the signaling proteins. Most are expressed at modest levels throughout the brain; the δ1 receptor is expressed more in the thalamus.

Oxytocin and vasopressin are nonapeptides, which diverged from a common signaling peptide before the mammalian radiation. Their receptors are G_q-proteins, which activate PI3K and open K⁺ channels, thus dampening neuron excitability. The two receptors diverged also early in vertebrate evolution, and the vasopressin receptor duplicated again in mammals; all three are distributed thinly in the brain. The Oxytocin gene is expressed abundantly in hypothalamus, and nowhere else, while its receptor (OXTR) is expressed in hypothalamus and sub-thalamic nucleus. The Vasopressin gene is expressed abundantly in hypothalamus, and nowhere else; it has two receptors: the AVPR1A receptor is expressed in some smooth muscle and the AVPR1B gene is expressed throughout the brain and in some peripheral tissues.

The HPA Axis

Corticotropin-releasing hormone (CRH) is a larger (41 aa) peptide, which is also manufactured together with oxytocin and vasopressin in the paraventricular nucleus of the hypothalamus. Its two receptors (CRHR1 & CRHR2) are highly conserved GPCR's which diverged prior to chordate evolution; they are distantly related to a diverse class of other GPCR's that respond to other peptides and hormones.

Both CRH receptors act by G_s type, but signaling is complex, because several splice variants of CRHR1 are expressed, and several do not seem to have cAMP-inducing activity. In some cells there seems to be actions mediated by PLC activity also. CRHR1 is moderately expressed in cortex and cerebellum. CRHR2 is moderately expressed in striatum and septum.