Table 1.
Brain-enriched and/or neurological-relevant GPCRs that can couple to the Gi/o subfamily, and their functions.
| Receptor classes | Gα protein | GPCRs’ ligand(s) and general functions; subtypes and their specific functions | |
|---|---|---|---|
| Adrenoceptors | α2A (ADRA2A) | Gi and Go | Ligand: Adrenaline > noradrenaline |
| • Their activation causes platelet aggregation, blood vessel constriction and constriction of vascular smooth muscle; | |||
| α2B (ADRA2B) | • Presynaptically, these receptors inhibit the release of noradrenaline (negative feedback control); | ||
| • α2B and α2C: positive regulation of neuronal differentiation. | |||
| α2C (ADRA2C) | |||
| Dopamine receptors | D2 (DRD2) | Gi/Go | Ligand: Dopamine |
| D3 (DRD3) | • Their activation mediates inhibitory dopaminergic neurotransmission; | ||
| D4 (DRD4) | D2: important in the reward effects of morphine; knockout mice exhibit abnormal synaptic plasticity and display reduced levels of aggression; adenohypophysis development; associative learning; axonogenesis; branching morphogenesis of nerves; cerebral cortex GABAergic interneuron migration; chemical synaptic transmission, postsynaptic; long-term memory; negative regulation of synaptic transmission, glutamatergic; neurological system process involved in regulation of systemic arterial blood pressure; neuron-neuron synaptic transmission; orbitofrontal cortex development; positive regulation of dopamine uptake involved in synaptic transmission; positive regulation of glial cell-derived neurotrophic factor secretion; positive regulation of long-term synaptic potentiation; positive regulation of neuroblast proliferation; prepulse inhibition; regulation of dopamine uptake involved in synaptic transmission; regulation of long-term neuronal synaptic plasticity; regulation of synapse structural plasticity; regulation of synaptic transmission, GABAergic; response to axon injury; striatum development; synapse assembly; synaptic transmission, dopaminergic; visual learning. | ||
| D3: their distribution is consistent with a role in cognition and emotional functions; implicated in modulation of cocaine self-administration; promotes cell proliferation; learning or memory; negative regulation of oligodendrocyte differentiation; prepulse inhibition; regulation of dopamine uptake involved in synaptic transmission; synaptic transmission, dopaminergic; visual learning. | |||
| D4: may be involved in the modulation of gastric acid secretion; responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior; modulates the circadian rhythm of contrast sensitivity and inhibits adrenergic receptor-induced melatonin synthesis by α(1B)-D4 and β1-D4 receptors heterodimerization; knockout mice are supersensitive to several psychoactive substances, including ethanol, cocaine, and methamphetamine; inhibitory postsynaptic potential; positive regulation of dopamine uptake involved in synaptic transmission. | |||
| Acetylcholine receptors | M2 (CHRM2) | Gi and Go | Ligand: Acetylcholine |
| M4 (CHRM4) | • Their activation mediates many of the effects of acetylcholine in the central and peripheral nervous system; | ||
| • Seem to function as autoreceptors; | |||
| • Knockout mice reveal an important neuromodulatory role for these receptors; | |||
| M2: control of myocyte contraction; smaller role in the smooth muscle contractile response; may be involved in the regulation of body temperature; nervous system development; synaptic transmission, cholinergic; | |||
| M4: inhibitory autoreceptor for acetylcholine; activation of the receptor in the striatum inhibits dopamine-induced locomotor stimulation in mice; synaptic transmission, cholinergic. | |||
| Serotonin receptors | 5-HT1A (HTR1A) | Gi/Go | Ligand: Serotonin |
| 5-HT1B (HTR1B) | • 5-HT1A: autoreceptors that inhibit cell firing; involved in many neuromodulative processes; implicated in the neuroendocrine regulation of adrenocorticotropic hormone (ACTH); role in the regulation of 5-hydroxytryptamine release, metabolism and levels in the brain – thereby affects neural activity, mood and behavior; plays a role in the response to anxiogenic stimuli; | ||
| 5-HT1D (HTR1D) | • 5-HT1B: induce presynaptic inhibition and influence behavior; vascular effects, such as pulmonary and cerebral arteries vasoconstriction; may also have a role in the regulation of bone; regulates the release of 5-hydroxytryptamine, dopamine and acetylcholine in the brain, and thereby affects neural activity, nociceptive processing, pain perception, mood and behavior; chemical synaptic transmission; negative regulation of synaptic transmission, GABAergic; negative regulation of synaptic transmission, glutamatergic; | ||
| 5-HT1E (HTR1E) | • 5-HT1D: affect locomotion and anxiety; involved in vascular vasoconstriction in the brain; implicated in feeding behavior, anxiety, depression; may have a stimulatory effect on growth hormone secretion; regulates the release of 5-hydroxytryptamine in the brain, and thereby affects neural activity; chemical synaptic transmission; | ||
| 5-HT1F (HTR1F) | • 5-HT1E: exact function is presently unknown, due to the lack of selective ligands; may have an important evolutionary role in humans and may be involved in the regulation of memory; chemical synaptic transmission; | ||
| 5-HT5A (HTR5A) | • 5-HT1F: chemical synaptic transmission; | ||
| • 5-HT5A: may play a role in sleep and serve as a presynaptic serotonin autoreceptor; chemical synaptic transmission. | |||
| Purinoceptors | P2Y12 (P2RY12) | Gi/Go | Ligand P2Y12 e P2Y13: ADP |
| Ligand P2Y14: UDP-glucose | |||
| P2Y13 (P2RY13) | P2Y12: role in amplification of platelet activation and aggregation and blood coagulation; glial cell migration; regulation of microglial cell migration; | ||
| P2Y14 (P2RY14) | P2Y13: may play a role in hematopoiesis and the immune system. | ||
| Opioid receptors | δ (DOR-1) | Gi and Go | Ligand delta (δ): β-Endorphin, met/leu-enkephalin |
| κ (KOR-1) | Gi/Go | Ligand kappa (κ): Dynorphin A | |
| μ (MOR-1) | Ligand mu (μ): β-Endorphin > Dynorphin A > met/leu-enkephalin | ||
| OPRL1 | Ligand OPRL1: Nociceptin/orphanin FQ | ||
| • δ: role in the perception of pain and in opiate-mediated analgesia; developing analgesic tolerance to morphine; chemical synaptic transmission; neuropeptide signaling pathway; | |||
| • κ: are believed to mediate analgesia and sedation (perception of pain), miosis and dieresis; role in mediating reduced physical activity and regulation of salivation upon treatment with synthetic opioids; may play a role in arousal and regulation of autonomic and neuroendocrine functions; chemical synaptic transmission; neuropeptide signaling pathway; | |||
| • μ: are believed to mediate analgesia, hypothermia, respiratory depression, miosis, bradycardia, nausea, euphoria, and physical dependence; involved in neurogenesis; chemical synaptic transmission; neuropeptide signaling pathway; positive regulation of neurogenesis; | |||
| • OPRL1: potential role in modulating various brain functions, including instinctive behaviors and emotions; role in modulating nociception and the perception of pain; regulation of locomotor activity by the neuropeptide nociception; chemical synaptic transmission; neuropeptide signaling pathway. | |||
| Somatostatin receptors | SSTR1 | Gi and Go | Ligand SSTR1-4: somatostatin-14 = somatostatin-28. |
| SSTR2 | Ligand SSTR5: somatostatin-28 > somatostatin-14. | ||
| SSTR3 | • SSTR1: cerebellum development; forebrain development; | ||
| SSTR4 | • SSTR2: growth hormone secretion; glucagon secretion; immune responses; mediates the inhibitory effect of somatostatin-14; inhibits cell growth; stimulates neuronal migration; stimulates axon outgrowth; neuronal development and maturation; mediates negative regulation of insulin receptor signaling through PTPN6; inactivates SSTR3 receptor function; cerebellum development; forebrain development; | ||
| SSTR5 | • SSTR3: inhibition of angiogenesis; cerebellum development; forebrain development; chemical synaptic transmission; neuropeptide signaling pathway; | ||
| • SSTR4: arachidonate release; activation of mitogen-activated protein kinase cascade; anti-proliferative action in tumor cells; cerebellum development; forebrain development; | |||
| • SSTR5: GH secretion; insulin secretion; increases cell growth; chemical synaptic transmission. | |||
| Angiotensin receptors | AT1 (AGTR1) | Gi/Go, Gq/11, G12/13 | Ligand: Angiotensin II > Angiotensin III |
| • Their activation mediates the cardiovascular effects of angiotensin II and angiotensin III (vasoconstriction, heart rate, aldosterone secretion, blood pressure, and volume); | |||
| • Regulation of cell proliferation. | |||
| Cannabinoid receptors | CB1 (CNR1) | Gi and Go | Ligand: Anandamide and 2-arachidonoyl glyceride |
| CB2 (CNR2) | • CB1: inhibition of ongoing release of excitatory and inhibitory neurotransmitters; axonal fasciculation; memory; negative regulation of action potential; positive regulation of neuron projection development; regulation of synaptic transmission, GABAergic and glutamatergic; trans-synaptic signaling by endocannabinoid, modulating synaptic transmission; negative regulation of dopamine secretion; | ||
| • CB2: effect on the immunological activity of leukocytes; immune suppression; induction of apoptosis; induction of cell migration; negative regulation of action potential; negative regulation of synaptic transmission, GABAergic. | |||
| Leukotriene receptors | LTB4R | Gi/Go and Gq/11 | Ligand: Leukotriene B4 |
| LTB4R2 | • LTB4R: may be the cardiac P2Y receptor involved in the regulation of cardiac muscle contraction; act as a co-receptor; for macrophage-tropic Human immunodeficiency virus 1 (HIV-1) strains; causes chemotaxis; neuropeptide signaling pathway; | ||
| • LTB4R2: mediates chemotaxis of granulocytes and macrophages; inhibit chemotaxis; neuropeptide signaling pathway. | |||
| Metabotropic GABA receptors | GABAB2 (GABBR2) | Gi and Go | Ligand: γ-Aminobutyric acid (GABA) |
| • Involved in the fine tuning of inhibitory synaptic transmission; pre-synaptic GABA receptor is an inhibitory neurotransmitter in the brain; postsynaptic GABA receptor decreases neuronal excitability; involved hippocampal long-term potentiation, slow wave sleep, muscle relaxation and anti-nociception; gamma-aminobutyric acid signaling pathway. | |||
| Metabotropic glutamate receptors | mGluR2 (GRM2) | Gi/Go | Ligand: Glutamate |
| mGluR3 (GRM3) | • mGluR2: may be involved in suppression of neurotransmission; may be involved in synaptogenesis or synaptic stabilization; chemical synaptic transmission; glutamate secretion; regulation of synaptic transmission, glutamatergic; | ||
| mGluR4 (GRM4) | • mGluR3: chemical synaptic transmission; regulation of synaptic transmission, glutamatergic; | ||
| • mGluR4: may have a role in modulation of glutamate transmission in the CNS; chemical synaptic transmission; neurotransmitter secretion; regulation of neuronal apoptotic process; regulation of synaptic transmission, glutamatergic; | |||
| mGluR6 (GRM6) | • mGluR6: may have an important function in some inherited eye diseases; required for normal vision; chemical synaptic transmission; regulation of synaptic transmission, glutamatergic; | ||
| mGluR7 (GRM7) | • mGluR7: may have a role in modulation of glutamate transmission in the CNS; chemical synaptic transmission; negative regulation of glutamate secretion; regulation of synaptic transmission, glutamatergic; sensory perception of smell; sensory perception of sound; short-term memory; transmission of nerve impulse; | ||
| mGluR8 (GRM8) | • mGluR8: presynaptic receptor may modulate glutamate release at the axon terminals of mitral/tufted cells in the entorhinal cortex; regulation of synaptic transmission, glutamatergic. | ||
| Oxytocin receptors∗ | OT (OXTR) | Gi/Go but mainly Gq/11 | Ligand: Oxytocin |
| • Stimulates contraction of uterine smooth muscle and of mammary gland; stimulates milk secretion in response to suckling; memory; positive regulation of synapse assembly, positive regulation of synaptic transmission, GABAergic and glutamatergic; positive regulation of norepinephrine secretion; sleep; social behavior. | |||
| Adenosine receptors∗ | A1 (ADORA1) | Gi/Go | Ligand: Adenosine |
| • A1: distributed widely in peripheral tissues where they have a mainly inhibitory role; cognition; excitatory postsynaptic potential; negative regulation of long term synaptic depression; negative regulation of mucus secretion; negative regulation of neurotrophin production; negative regulation of synaptic transmission, GABAergic; negative regulation of synaptic transmission, glutamatergic; nervous system development; regulation of respiratory gaseous exchange by neurological system process; | |||
| • A3: may play a role in reproduction. | |||
∗The protein levels of these receptors in the brain were not reported in the Human Protein Atlas. However, as these GPCRs are known to play important functions in the brain, and their protein levels decrease with age, they were also included in this analysis. Data was taken from UniProt (The UniProt Consortium, 2017) and InterPro (Petryszak et al., 2016) database and included brain related Gene Ontology (GO) annotations (Molecular functions and Biological processes). ‘Gi and Go’, GPCRs that couple with both Gi and Go proteins; ‘Gi/Go’, GPCRs known to couple with at least one of these Gα proteins (Gimpl and Fahrenholz, 2001; Guo et al., 2001; Hunyady and Catt, 2006; Peres et al., 2007; Svízenská et al., 2008; Jiang and Bajpayee, 2009; McQuail et al., 2013).