Metabotropic receptor

Type of membrane receptor that acts through a second messenger

A metabotropic receptor, also referred to by the broader term G-protein-coupled receptor,[1] is a type of membrane receptor that initiates a number of metabolic steps to modulate cell activity. The nervous system utilizes two types of receptors: metabotropic and ionotropic receptors. While ionotropic receptors form an ion channel pore, metabotropic receptors are indirectly linked with ion channels through signal transduction mechanisms, such as G proteins. These two types of receptors, along with their number and activity level, form the basis of the sympathetic and parasympathetic nervous systems and play key roles in regulating rates of resting energy expenditure (REE), resting heart rate, heart rate variability, and global myocardial oxygen consumption.

Both receptor types are activated by specific chemical ligands. When an ionotropic receptor is activated, it opens a channel that allows ions such as Na+, K+, or Cl− to flow. In contrast, when a metabotropic receptor is activated, a series of intracellular events are triggered that can also result in ion channels opening or other intracellular events, but involve a range of second messenger chemicals.[2]

## Mechanism

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Chemical messengers bind to metabotropic receptors to initiate a diversity of effects caused by biochemical signaling cascades. G protein-coupled receptors are all metabotropic receptors. When a ligand binds to a G protein-coupled receptor, a guanine nucleotide-binding protein, or G protein, activates a second messenger cascade which can alter gene transcription, regulate other proteins in the cell, release intracellular Ca2+, or directly affect ion channels on the membrane.[3][4] These receptors can remain open from seconds to minutes and are associated with long-lasting effects, such as modifying synaptic strength and modulating short- and long-term synaptic plasticity.[5]

Metabotropic receptors have a diversity of ligands, including but not limited to: small molecule transmitters, monoamines, peptides, hormones, and even gases.[5][6][7] In comparison to fast-acting neurotransmitters, these ligands are not taken up again or degraded quickly. They can also enter the circulatory system to globalize a signal.[3] Most metabotropic ligands have unique receptors. Some examples include: metabotropic glutamate receptors, muscarinic acetylcholine receptors, GABAB receptors.[2][8]

## Structure

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The G protein-coupled receptors have seven hydrophobic transmembrane domains. Most of them are monomeric proteins, although GABAB receptors require heterodimerization to function properly. The protein's N terminus is located on the extracellular side of the membrane and its C terminus is on the intracellular side.[2]

The 7 transmembrane spanning domains, with an external amino terminus, are often claimed as being alpha helix shaped, and the polypeptide chain is said to be composed of around 450-550 amino acids.

## References

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1. ^ Purves, Dale, ed. (2018). Neuroscience, 6th ed. Sunderland, Mass: Sinauer Associates. p. 103.
2. ^ a b c Williams, S. J.; Purves, Dale (2001). Neuroscience. Sunderland, Mass: Sinauer Associates. ISBN 0-87893-742-0.
3. ^ a b "Principles of Neural Design", The MIT Press, 2015, doi:10.7551/mitpress/9395.003.0019, ISBN 978-0-262-32731-2, retrieved October 18, 2020 `{{citation}}`: Missing or empty `|title=` (help)
4. ^ Ferguson, Duncan C. (January 1, 2018), Wallig, Matthew A.; Haschek, Wanda M.; Rousseaux, Colin G.; Bolon, Brad (eds.), "Chapter 4 - Principles of Pharmacodynamics and Toxicodynamics", Fundamentals of Toxicologic Pathology (Third Edition), Academic Press, pp. 47–58, doi:10.1016/b978-0-12-809841-7.00004-6, ISBN 978-0-12-809841-7, retrieved October 30, 2020
5. ^ a b Nadim, Farzan; Bucher, Dirk (December 2014). "Neuromodulation of Neurons and Synapses". Current Opinion in Neurobiology. 29: 48–56\. doi:10.1016/j.conb.2014.05.003. ISSN 0959-4388. PMC 4252488. PMID 24907657.
6. ^ Burrows, Malcolm (1996). "Neurotransmitters, neuromodulators and neurohormones". The Neurobiology of an Insect Brain. Oxford Scholarship. doi:10.1093/acprof:oso/9780198523444.003.0005. ISBN 9780198523444.
7. ^ Marder, Eve (October 4, 2012). "Neuromodulation of Neuronal Circuits: Back to the Future". Neuron. 76 (1): 1–11\. doi:10.1016/j.neuron.2012.09.010. ISSN 0896-6273. PMC 3482119. PMID 23040802.
8. ^ Hoehn K, Marieb EN (2007). "Fundamentals of the nervous system and nervous tissue". Human Anatomy & Physiology. San Francisco: Pearson Benjamin Cummings. ISBN 978-0-8053-5910-7.

## Further reading

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* Zimmerberg, B. 2002. Dopamine receptors: A representative family of metabotropic receptors. Multimedia Neuroscience Education Project [1]

* v
* t
* e

Cell surface receptor: G protein-coupled receptors

Class A: Rhodopsin-like

| Neurotransmitter|

| Adrenergic|

* α1 (A
* B
* D)
* α2 (A
* B
* C)
* β1
* β2
* β3

|

Purinergic|

* Adenosine (A1
* A2A
* A2B
* A3)
* P2Y (1
* 2
* 4
* 5
* 6
* 8
* 9
* 10
* 11
* 12
* 13
* 14)

Serotonin|

* (all but 5-HT3) 5-HT1 (A
* B
* D
* E
* F)
* 5-HT2 (A
* B
* C)
* 5-HT (4
* 5A
* 6
* 7)

Other|

* Acetylcholine (M1
* M2
* M3
* M4
* M5)
* Dopamine
* D1
* D2
* D3
* D4
* D5
* GHB receptor
* Histamine
* H1
* H2
* H3
* H4
* Melatonin (1A
* 1B
* 1C)
* TAAR (1
* 2
* 5
* 6
* 8
* 9)

Metabolites and
signaling molecules|

| Eicosanoid|

* CysLT (1
* 2)
* LTB4
* 1
* 2
* FPRL1
* OXE
* Prostaglandin
* DP (1
* 2), EP (1
* 2
* 3
* 4), FP
* Prostacyclin
* Thromboxane

|

Other|

* Bile acid
* Cannabinoid (CB1
* CB2, GPR (18
* 55
* 119))
* EBI2
* Estrogen
* Free fatty acid (1
* 2
* 3
* 4)
* Hydroxycarboxylic acids
* 1
* 2
* 3
* Lysophosphatidic acid (1
* 2
* 3
* 4
* 5
* 6)
* Lysophospholipid (1
* 2
* 3
* 4
* 5
* 6
* 7
* 8)
* Oxoglutarate
* PAF
* Sphingosine-1-phosphate (1
* 2
* 3
* 4
* 5)
* Succinate

Peptide|

| Neuropeptide|

* B/W (1
* 2)
* FF (1
* 2)
* S
* Y (1
* 2
* 4
* 5)
* Neuromedin (B
* U (1
* 2))
* Neurotensin (1
* 2)

|

Other|

* Anaphylatoxin (C3a
* C5a (1
* 2))
* Angiotensin (1
* 2)
* Apelin
* Bombesin
* BRS3
* GRPR
* NMBR)
* Bradykinin (B1
* B2)
* Chemerin
* 1
* 2
* Chemokine
* Cholecystokinin (A
* B)
* Endothelin
* A
* B
* Formyl peptide (1
* 2
* 3)
* FSH
* Galanin (1
* 2
* 3)
* Gonadotropin-releasing hormone (1
* 2)
* Ghrelin
* Kisspeptin
* Luteinizing hormone/choriogonadotropin
* MAS (1
* 1L
* D
* E
* F
* G
* X1
* X2
* X3
* X4)
* Melanocortin (1
* 2
* 3
* 4
* 5)
* MCHR (1
* 2)
* Motilin
* Opioid (Delta
* Kappa
* Mu
* Nociceptin & Zeta, but not Sigma)
* Orexin (1
* 2)
* Oxytocin
* Prokineticin (1
* 2)
* Prolactin-releasing peptide
* Relaxin (1
* 2
* 3
* 4)
* Somatostatin (1
* 2
* 3
* 4
* 5)
* Tachykinin (1
* 2
* 3)
* Thyrotropin
* Thyrotropin-releasing hormone
* Urotensin-II
* Vasopressin (1A
* 1B
* 2)

Miscellaneous|

| Taste, bitter|

* TAS2R
* 1
* 3
* 4
* 5
* 7
* 8
* 9
* 10
* 13
* 14
* 16
* 19
* 20
* 30
* 31
* 38
* 39
* 40
* 41
* 42
* 43
* 45
* 46
* 50
* 60
* Vomeronasal receptor type 1

|

Orphan|

* GPR (3
* 4
* 6
* 12
* 15
* 17
* 18
* 19
* 20
* 21
* 22
* 26
* 27
* 31
* 32
* 33
* 34
* 35
* 37
* 39
* 42
* 45
* 50
* 52
* 55
* 61
* 62
* 63
* 65
* 68
* 75
* 78
* 82
* 83
* 84
* 85
* 87
* 88
* 101
* 103
* 109A
* 109B
* 119
* 120
* 132
* 135
* 137B
* 139
* 141
* 142
* 146
* 148
* 149
* 150
* 151
* 152
* 153
* 160
* 161
* 162
* 171
* 173
* 174
* 176
* 177
* 182
* 183)

Other|

* Adrenomedullin
* Olfactory
* Opsin (3
* 4
* 5
* 1LW
* 1MW
* 1SW
* RGR
* RRH)
* Protease-activated (1
* 2
* 3
* 4)
* SREB (1
* 2
* 3)

Class B: Secretin-like

| Adhesion|

* ADGRB
* Brain-specific angiogenesis inhibitor
* 1
* 2
* 3
* ADGRC
* Cadherin
* 1
* 2
* 3
* ADGRE
* EMR
* 1
* 2
* 3
* CD97
* ADGRG
* 1
* 2
* 3
* 4
* 5
* 6
* 7
* ADGRL
* Latrophilin
* 1
* 2
* 3
* ELTD1

|

Orphan|

* GPR (56
* 64
* 97
* 98
* 110
* 111
* 112
* 113
* 114
* 115
* 116
* 123
* 124
* 125
* 126
* 128
* 133
* 143
* 144
* 155
* 157)

Other|

* Calcitonin
* CALCRL
* Corticotropin-releasing hormone (1
* 2)
* Glucagon (GR
* GIPR
* GLP1R
* GLP2R)
* Growth-hormone-releasing hormone
* PACAPR1
* GPR
* Methuselah-like proteins
* Parathyroid hormone (1
* 2)
* Secretin
* Vasoactive intestinal peptide (1
* 2)

Class C: Metabotropic glutamate / pheromone

| Taste, sweet|

* TAS1R
* 1
* 2
* 3
* Vomeronasal receptor, type 2

|

Other|

* Calcium-sensing receptor
* GABAB (1
* 2)
* Glutamate receptor (Metabotropic glutamate (1
* 2
* 3
* 4
* 5
* 6
* 7
* 8))
* GPRC6A
* GPR (156
* 158
* 179)
* RAIG (1
* 2
* 3
* 4)

Class F: Frizzled & Smoothened

| Frizzled|

* Frizzled (1
* 2
* 3
* 4
* 5
* 6
* 7
* 8
* 9
* 10)

|

Smoothened|

* Smoothened

* v
* t
* e

Protein kinases: tyrosine kinases (EC 2.7.10)

Receptor tyrosine kinases (EC 2.7.10.1)

| Growth factor receptors|

| EGF receptor family|

* EGFR
* ERBB2
* ERBB3
* ERBB4

|

Insulin receptor family|

* IGF1R
* INSR
* INSRR

PDGF receptor family|

* CSF1R
* FLT3
* KIT
* PDGFR (PDGFRA
* PDGFRB)

FGF receptor family|

* FGFR1
* FGFR2
* FGFR3
* FGFR4

VEGF receptors family|

* VEGFR1
* VEGFR2
* VEGFR3

HGF receptor family|

* MET
* RON

Trk receptor family|

* NTRK1
* NTRK2
* NTRK3

EPH receptor family|

* EPHA1
* EPHA2
* EPHA3
* EPHA4
* EPHA5
* EPHA6
* EPHA7
* EPHA8
* EPHB1
* EPHB2
* EPHB3
* EPHB4
* EPHB5
* EPHB6
* EPHX

LTK receptor family|

* LTK
* ALK

TIE receptor family|

* TIE
* TEK

ROR receptor family|

* ROR1
* ROR2

DDR receptor family|

* DDR1
* DDR2

PTK7 receptor family|

* PTK7

RYK receptor family|

* RYK

MuSK receptor family|

* MUSK

ROS receptor family|

* ROS1

AATYK receptor family|

* AATYK
* AATYK2

AXL receptor family|

* AXL
* MER
* TYRO3

RET receptor family|

* RET

uncategorised|

* STYK1

Non-receptor tyrosine kinases (EC 2.7.10.2)

| ABL family|

* ABL1
* ARG

|

ACK family|

* ACK1
* TNK1

CSK family|

* CSK
* MATK

FAK family|

* FAK
* PYK2

FES family|

* FES
* FER

FRK family|

* FRK
* BRK
* SRMS

JAK family|

* JAK1
* JAK2
* JAK3
* TYK2

SRC-A family|

* SRC
* FGR
* FYN
* YES1

SRC-B family|

* BLK
* HCK
* LCK
* LYN

TEC family|

* TEC
* BMX
* BTK
* ITK
* TXK

SYK family|

* SYK
* ZAP70

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