Ligand-gated ion channel

Neurotransmitter-gated ion-channel transmembrane region
Ligand-gated ion channel
Identifiers
Symbol	Neur_chan_memb
Pfam	PF02932
InterPro	IPR006029
PROSITE	PDOC00209
SCOP	1cek
TCDB	1.A.9
OPM family	14
OPM protein	2bg9
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Neurotransmitter-gated ion-channel ligand binding domain
Identifiers
Symbol	Neur_chan_LBD
Pfam	PF02931
InterPro	IPR006202
PROSITE	PDOC00209
SCOP	1lxg
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Ligand-gated ion channels (LGICs) are one type of ionotropic receptor or channel-linked receptor. They are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger (i.e., a ligand),^[1] such as a neurotransmitter.^[2]

The binding site of endogenous ligands on LGICs protein complexes are normally located on a different portion of the protein (an allosteric binding site) compared to where the ion conduction pore is located. The direct link between ligand binding and opening or closing of the ion channel, which is characteristic of ligand-gated ion channels, is contrasted with the indirect function of metabotropic receptors, which use second messengers. LGICs are also different from voltage-gated ion channels (which open and close depending on membrane potential), and stretch-activated ion channels (which open and close depending on mechanical deformation of the cell membrane).^[2][3]

Regulation

The ion channel is regulated by a ligand and is usually very selective to one or more ions like Na⁺, K⁺, Ca²⁺, or Cl^-. Such receptors located at synapses convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal.

Many LGICs are additionally modulated by allosteric ligands, by channel blockers, ions, or the membrane potential.

Structure

Each subunit of the pentameric channels consist of the extracellular ligand-binding domain and a transmembrane domain. Each transmembrane domain in the pentamer includes four transmembrane helixes.^[4]

Example: nicotinic acetylcholine receptor

The prototypic ligand-gated ion channel is the nicotinic acetylcholine receptor. It consists of a pentamer of protein subunits, with two binding sites for acetylcholine, which, when bound, alter the receptor's configuration and cause an internal pore to open. This pore allowed Na⁺ ions to flow down their electrochemical gradient into the cell. With a sufficient number of channels opening at once, the intracellular Na⁺ concentration rises to the point at which the positive charge within the cell is enough to depolarize the membrane, and an action potential is initiated.

Classification

Many important ion channels are ligand-gated, and they show a significant degree of homology at the genetic level. LGICs are classified into three superfamilies:

Cys-loop receptors

The cys-loop receptors contain a characteristic loop formed by a disulfide bond between two cysteine residues and are subdivided into the type of ion that the corresponding channel conducts (anionic or cationic) and further into families defined by the endogenous ligand. They are usually pentameric.

Vertebrate Anionic Cys-loop Receptors

Type	Class	IUPHAR-recommended protein name[5]	Gene	Previous names
GABAA	alpha	α1 α2 α3 α4 α5 α6	GABRA1 GABRA2 GABRA3 GABRA4 GABRA5 GABRA6	EJM, ECA4
	beta	β1 β2 β3	GABRB1 GABRB2 GABRB3	ECA5
	gamma	γ1 γ2 γ3	GABRG1 GABRG2 GABRG3	CAE2, ECA2, GEFSP3
	delta	δ	GABRD
	epsilon	ε	GABRE
	pi	π	GABRP
	theta	θ	GABRQ
	rho	ρ1 ρ2 ρ3	GABRR1 GABRR2 GABRR3	GABAC[6]
Glycine (GlyR)	alpha	α1 α2 α3 α4	GLRA1 GLRA2 GLRA3 GLRA4	STHE
	beta	β	GLRB

Vertebrate Cationic Cys-loop Receptors

Type	Class	IUPHAR-recommended protein name [5]	Gene	Previous names
Serotonin (5-HT)	5-HT3	5-HT3A 5-HT3B 5-HT3C 5-HT3D 5-HT3E	HTR3A HTR3B HTR3C HTR3D HTR3E	5-HT3A 5-HT3B 5-HT3C 5-HT3D 5-HT3E
Nicotinic acetylcholine (nAChR)	alpha	α1 α2 α3 α4 α5 α6 α7 α9 α10	CHRNA1 CHRNA2 CHRNA3 CHRNA4 CHRNA5 CHRNA6 CHRNA7 CHRNA9 CHRNA10	ACHRA, ACHRD, CHRNA, CMS2A, FCCMS, SCCMS
	beta	β1 β2 β3 β4	CHRNB1 CHRNB2 CHRNB3 CHRNB4	CMS2A, SCCMS, ACHRB, CHRNB, CMS1D EFNL3, nAChRB2
	gamma	γ	CHRNG	ACHRG
	delta	δ	CHRND	ACHRD, CMS2A, FCCMS, SCCMS
	epsilon	ε	CHRNE	ACHRE, CMS1D, CMS1E, CMS2A, FCCMS, SCCMS
Zinc-activated ion channel (ZAC)		ZAC	ZACN	ZAC1, L2m LGICZ, LGICZ1

Ionotropic glutamate receptors

The ionotropic glutamate receptors bind the neurotransmitter glutamate. They form tetramers.

Type	Class	IUPHAR-recommended protein name [5]	Gene	Previous names
AMPA	GluA	GluA1 GluA2 GluA3 GluA4	GRIA1 GRIA2 GRIA3 GRIA4	GLUA1, GluR1, GluRA, GluR-A, GluR-K1, HBGR1 GLUA2, GluR2, GluRB, GluR-B, GluR-K2, HBGR2 GLUA3, GluR3, GluRC, GluR-C, GluR-K3 GLUA4, GluR4, GluRD, GluR-D
Kainate	GluK	GluK1 GluK2 GluK3 GluK4 GluK5	GRIK1 GRIK2 GRIK3 GRIK4 GRIK5	GLUK5, GluR5, GluR-5, EAA3 GLUK6, GluR6, GluR-6, EAA4 GLUK7, GluR7, GluR-7, EAA5 GLUK1, KA1, KA-1, EAA1 GLUK2, KA2, KA-2, EAA2
NMDA	GluN	GluN1 NRL1A NRL1B	GRIN1 GRINL1A GRINL1B	GLUN1, NMDA-R1, NR1, GluRξ1
		GluN2A GluN2B GluN2C GluN2D	GRIN2A GRIN2B GRIN2C GRIN2D	GLUN2A, NMDA-R2A, NR2A, GluRε1 GLUN2B, NMDA-R2B, NR2B, hNR3, GluRε2 GLUN2C, NMDA-R2C, NR2C, GluRε3 GLUN2D, NMDA-R2D, NR2D, GluRε4
		GluN3A GluN3B	GRIN3A GRIN3B	GLUN3A, NMDA-R3A, NMDAR-L, chi-1 GLU3B, NMDA-R3B
‘Orphan’	(GluD)	GluD1 GluD2	GRID1 GRID2	GluRδ1 GluRδ2

ATP-gated channels

Main article: P2X receptor

ATP-gated channels open in response to binding the nucleotide ATP. They form trimers.

Type	Class	IUPHAR-recommended protein name [5]	Gene	Previous names
P2X	N/A	P2X1 P2X2 P2X3 P2X4 P2X5 P2X6 P2X7	P2RX1 P2RX2 P2RX3 P2RX4 P2RX5 P2RX6 P2RX7	P2X1 P2X2 P2X3 P2X4 P2X5 P2X6 P2X7

Clinical relevance

Ligand-gated ion channels are likely to be the major site at which anaesthetic agents and ethanol have their effects, although unequivocal evidence of this is yet to be established.^[7][8] In particular, the GABA and NMDA receptors are affected by anaesthetic agents at concentrations similar to those used in clinical anaesthesia.^[9]

See also

Neuroscience portal

Chronotropic Receptor (biochemistry) Glycine receptor

P2X Receptor Sodium ion channel

References

1. ^ "ligand-gated channel" at Dorland's Medical Dictionary
2. ^ ^{a b} Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008). Neuroscience. 4th ed.. Sinauer Associates. pp. 156–7. ISBN 978-0-87893-697-7. 
3. ^ Connolly CN, Wafford KA (2004). "The Cys-loop superfamily of ligand-gated ion channels: the impact of receptor structure on function". Biochem. Soc. Trans. 32 (Pt3): 529–34. doi:10.1042/BST0320529. PMID 15157178. 
4. ^ Cascio M (2004). "Structure and function of the glycine receptor and related nicotinicoid receptors". J. Biol. Chem. 279 (19): 19383–6. doi:10.1074/jbc.R300035200. PMID 15023997. 
5. ^ ^{a b c d} Collingridge GL, Olsen RW, Peters J, Spedding M (January 2009). "A nomenclature for ligand-gated ion channels". Neuropharmacology 56 (1): 2–5. doi:10.1016/j.neuropharm.2008.06.063. PMC 2847504. PMID 18655795. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2847504. 
6. ^ Olsen RW, Sieghart W (September 2008). "International Union of Pharmacology. LXX. Subtypes of γ-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update". Pharmacol. Rev. 60 (3): 243–60. doi:10.1124/pr.108.00505. PMC 2847512. PMID 18790874. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2847512. 
7. ^ Krasowski MD, Harrison NL (1999). "General anaesthetic actions on ligand-gated ion channels". Cell. Mol. Life Sci. 55 (10): 1278–303. doi:10.1007/s000180050371. PMC 2854026. PMID 10487207. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2854026. 
8. ^ Dilger JP (2002). "The effects of general anaesthetics on ligand-gated ion channels". Br J Anaesth 89 (1): 41–51. doi:10.1093/bja/aef161. PMID 12173240. 
9. ^ Harris RA, Mihic SJ, Dildy-Mayfield JE, Machu TK (1995). "Actions of anesthetics on ligand-gated ion channels: role of receptor subunit composition" (abstract). FASEB J. 9 (14): 1454–62. PMID 7589987. http://www.fasebj.org/cgi/content/abstract/9/14/1454. 

External links

• Ligand-Gated Ion Channel database at European Bioinformatics Institute. Verified availability April 11, 2007.
• "Revised Recommendations for Nomenclature of Ligand-Gated Ion Channels". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/LGICNomenclature.jsp.