Ligand-gated ion channel

Ligand-gated ion channels (LICs, LGIC^[1]), (TC# 1.A.9), also commonly referred as ionotropic receptors, are a group of transmembrane ion channel proteins which open to allow ions such as Na⁺, K⁺, Ca²⁺, and/or Cl⁻ to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand),^[2] such as a neurotransmitter.^[3]

When a presynaptic neuron is excited, it releases neurotransmitter from vesicles into the synaptic cleft. The neurotransmitter then binds to receptors located on the postsynaptic neuron. If these receptors are ligand-gated ion channels, a resulting conformational change opens the ion channels, which leads to a flow of ions across the cell membrane. This, in turn, results in either a depolarization, for an excitatory receptor response, or a hyperpolarization, for an inhibitory response.

These proteins are typically composed of at least two different domains: a transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location (an allosteric binding site). This modularity has enabled a 'divide and conquer' approach to finding the structure of the proteins (crystallising each domain separately). The function of such receptors located at synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands, by channel blockers, ions, or the membrane potential. LICs are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels.

Cys-loop receptors

Nicotinic acetylcholine receptor in closed state with predicted membrane boundaries shown, PDB 2BG9

The cys-loop receptors are named after a characteristic loop formed by a disulfide bond between two cysteine residues in the N terminal extracellular domain. They are part of a larger family of pentameric ligand-gated ion channels that usually lack this disulfide bond, hence the tentative name "Pro-loop receptors".^[4]^[5] A binding site in the extracellular N-terminal ligand-binding domain gives them receptor specificity for (1) acetylcholine (AcCh), (2) serotonin, (3) glycine, (4) glutamate and (5) γ-aminobutyric acid (GABA) in vertebrates. The receptors are subdivided with respect to the type of ion that they conduct (anionic or cationic) and further into families defined by the endogenous ligand. They are usually pentameric with each subunit containing 4 transmembrane helices constituting the transmembrane domain, and a beta sheet sandwich type, extracellular, N terminal, ligand binding domain.^[6] Some also contain an intracellular domain like shown in the image.

The prototypic ligand-gated ion channel is the nicotinic acetylcholine receptor. It consists of a pentamer of protein subunits (typically ααβγδ), with two binding sites for acetylcholine (one at the interface of each alpha subunit). When the acetylcholine binds it alters the receptor's configuration (twists the T2 helices which moves the leucine residues, which block the pore, out of the channel pathway) and causes the constriction in the pore of approximately 3 angstroms to widen to approximately 8 angstroms so that ions can pass through. This pore allows Na⁺ ions to flow down their electrochemical gradient into the cell. With a sufficient number of channels opening at once, the inward flow of positive charges carried by Na⁺ ions depolarizes the postsynaptic membrane sufficiently to initiate an action potential.

While single-cell organisms like bacteria would have little apparent need for the transmission of an action potential, a bacterial homologue to an LIC has been identified, hypothesized to act nonetheless as a chemoreceptor.^[4] This prokaryotic nAChR variant is known as the GLIC receptor, after the species in which it was identified; Gloeobacter Ligand-gated Ion C channel.

Structure

Cys-loop receptors have structural elements that are well conserved, with a large extracellular domain (ECD) harboring an alpha-helix and 10 beta-strands. Following the ECD, four transmembrane segments (TMSs) are connected by intracellular and extracellular loop structures.^[7] Except the TMS 3-4 loop, their lengths are only 7-14 residues. The TMS 3-4 loop forms the largest part of the intracellular domain (ICD) and exhibits the most variable region between all of these homologous receptors. The ICD is defined by the TMS 3-4 loop together with the TMS 1-2 loop preceding the ion channel pore.^[7] Crystallization has revealed structures for some members of the family, but to allow crystallization, the intracellular loop was usually replaced by a short linker present in prokaryotic cys-loop receptors, so their structures as not known. Nevertheless, this intracellular loop appears to function in desensitization, modulation of channel physiology by pharmacological substances, and posttranslational modifications. Motifs important for trafficking are therein, and the ICD interacts with scaffold proteins enabling inhibitory synapse formation.^[7]

Cationic cys-loop receptors

Type	Class	IUPHAR-recommended protein name ^[8]	Gene	Previous names
Serotonin (5-HT)	5-HT₃	5-HT3A 5-HT3B 5-HT3C 5-HT3D 5-HT3E	HTR3A HTR3B HTR3C HTR3D HTR3E	5-HT_3A 5-HT_3B 5-HT_3C 5-HT_3D 5-HT_3E
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 LICZ, LICZ1

Anionic cys-loop receptors

Type	Class	IUPHAR-recommended protein name^[8]	Gene	Previous names
GABA_A	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	GABA_C^[9]
Glycine (GlyR)	alpha	α1 α2 α3 α4	GLRA1 GLRA2 GLRA3 GLRA4	STHE
Glycine (GlyR)	beta	β	GLRB

Ionotropic glutamate receptors

The AMPA receptor bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, PDB 3KG2

The ionotropic glutamate receptors bind the neurotransmitter glutamate. They form tetramers with each subunit consisting of an extracellular amino terminal domain (ATD, which is involved tetramer assembly), an extracellular ligand binding domain (LBD, which binds glutamate), and a transmembrane domain (TMD, which forms the ion channel). The transmembrane domain of each subunit contains three transmembrane helices as well as a half membrane helix with a reentrant loop. The structure of the protein starts with the ATD at the N terminus followed by the first half of the LBD which is interrupted by helices 1,2 and 3 of the TMD before continuing with the final half of the LBD and then finishing with helix 4 of the TMD at the C terminus. This means there are three links between the TMD and the extracellular domains. Each subunit of the tetramer has a binding site for glutamate formed by the two LBD sections forming a clamshell like shape. Only two of these sites in the tetramer need to be occupied to open the ion channel. The pore is mainly formed by the half helix 2 in a way which resembles an inverted potassium channel.

Type	Class	IUPHAR-recommended protein name ^[8]	Gene	Previous names
AMPA	GluA	GluA1 GluA2 GluA3 GluA4	GRIA1 GRIA2 GRIA3 GRIA4	GLU_A1, GluR1, GluRA, GluR-A, GluR-K1, HBGR1 GLU_A2, GluR2, GluRB, GluR-B, GluR-K2, HBGR2 GLU_A3, GluR3, GluRC, GluR-C, GluR-K3 GLU_A4, GluR4, GluRD, GluR-D
Kainate	GluK	GluK1 GluK2 GluK3 GluK4 GluK5	GRIK1 GRIK2 GRIK3 GRIK4 GRIK5	GLU_K5, GluR5, GluR-5, EAA3 GLU_K6, GluR6, GluR-6, EAA4 GLU_K7, GluR7, GluR-7, EAA5 GLU_K1, KA1, KA-1, EAA1 GLU_K2, KA2, KA-2, EAA2
NMDA	GluN	GluN1 NRL1A NRL1B	GRIN1 GRINL1A GRINL1B	GLU_N1, NMDA-R1, NR1, GluRξ1
		GluN2A GluN2B GluN2C GluN2D	GRIN2A GRIN2B GRIN2C GRIN2D	GLU_N2A, NMDA-R2A, NR2A, GluRε1 GLU_N2B, NMDA-R2B, NR2B, hNR3, GluRε2 GLU_N2C, NMDA-R2C, NR2C, GluRε3 GLU_N2D, NMDA-R2D, NR2D, GluRε4
		GluN3A GluN3B	GRIN3A GRIN3B	GLU_N3A, NMDA-R3A, NMDAR-L, chi-1 GLU_3B, NMDA-R3B
‘Orphan’	(GluD)	GluD1 GluD2	GRID1 GRID2	GluRδ1 GluRδ2

AMPA receptor

The AMPA receptor bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, PDB 3KG2

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, or quisqualate receptor) is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS). Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen.^[10] AMPARs are found in many parts of the brain and are the most commonly found receptor in the nervous system. The AMPA receptor GluA2 (GluR2) tetramer was the first glutamate receptor ion channel to be crystallized.

AMPA receptor trafficking

Ligands:

Agonists: Glutamate, AMPA, 5-Fluorowillardiine, Domoic acid, Quisqualic acid, etc.
Antagonists: CNQX, Ethanol, Kynurenic acid, NBQX, Perampanel, Piracetam, etc.
Positive allosteric modulators: Aniracetam, Cyclothiazide, CX-516, CX-614, etc.
Negative allosteric modulators: Perampanel, Talampanel, GYKI-52,466, etc.

NMDA receptors

Stylized depiction of an activated NMDAR

The N-methyl-D-aspartate receptor (NMDA receptor) is a type of ionotropic glutamate receptor, also a known voltage-gated ion channel. Studies show that it is related to synaptic plasticity and memory.^[11]^[12]
NMDA(N-methyl-D-aspartate) is a type of agonist that could specifically bind to NMDA receptors; it activates the receptor to open the cation channel. It allows Na⁺ and a small amount of Ca²⁺ to flow into the cell, which rises the potential. Thus, it is an excitatory receptor. As a voltage-gated ion channel, at resting potentials, most subtypes of NMDA receptor would block by extracellular Mg2+ and Zn2+ , which reduces the synaptic currents. "However, when neurons are depolarized, for example, by intense activation of colocalized postsynaptic AMPA receptors, the voltage-dependent block by Mg2+ is partially relieved, allowing ion influx through activated NMDA receptors. The resulting Ca2+ influx can trigger a variety of intracellular signaling cascades, which can ultimately change neuronal function through activation of various kinases and phosphatases".^[13]
Ligands:

Agonists : Aminocyclopropanecarboxylic acid; D-Cycloserine; L-Aspartate; Quinolinate, etc.
Partial agonists : N-Methyl-D-aspartic acid (NMDA); NRX-1074; 3,5-dibromo-L-phenylalanine,^[14] etc.
Antagonists : Ethanol; Ketamine; PCP; Dextropropoxyphene; Ketobemidone; Tramadol, Kynurenic acid(endogenous), etc.

GABA receptors

GABA receptors are major inhibitory neurotransmitter expressed in the major interneurons in animal cortex.

GABA_A receptor

GABAA receptor schematic

GABAA receptors are ligand-gated ion channels. GABA (γ-amino butyric acid) being its endogenous ligand, is the major inhibitory neurotransmitter in central nervous system. When activated, it facilitates Cl- flow into the neuron, decrease the potential inside neuron, creating hyperpolarization effect. GABAA receptors occur in all organisms that have a nervous system. To a limited extent the receptors can be found in non-neuronal tissues. Due to their wide distribution within the nervous system of mammals they play a role in virtually all brain functions.

Research shows a series of ligands can specifically bind to GABAA receptor, activate/block the channel. Ligands:

Agonists: GABA, muscimol, progabide, gaboxadol, etc.
Antagonists: bicuculine, gabazine, etc.
Partial agonist:piperidine-4-sulfonic acid, etc.

5-HT receptors

3D structure model of the 5-HT1B receptor in complex with ergotamine based on crystallographic data for PDB 4IAR

5-HT receptors, also known as the serotonin receptors, or 5-hydroxytryptamine receptors, are ligand-gated ion channels. They activate an intracellular second messenger cascade to produce an excitatory/inhibitory response. They are found in mammals, both central nervous system (CNS) and peripheral nervous system (PNS), as well as other animals.^[15] Its natural ligand is Serotonin, and it modulates the release of multiple neurotransmitters, such as dopamine, epinephrine/norepinephrine, glutamate, and GABA.
Research confirm that the 5-HT receptors are involved in many neurological processes, such as anxiety, depression, sleep, cognition, memory, and so on. Thus there are several drugs targeting the 5-HT system, including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs, as well as the psychedelic drugs and empathogens.^[16]^[17]^[18]

ATP-gated channels

Figure 1. Schematic representation showing the membrane topology of a typical P2X receptor subunit. First and second transmembrane domains are labeled TM1 and TM2.

ATP-gated channels open in response to binding the nucleotide ATP. They form trimers with two transmembrane helices per subunit and both the C and N termini on the intracellular side.

Type	Class	IUPHAR-recommended protein name ^[8]	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

PIP₂-gated channels

Phosphatidylinositol 4,5-bisphosphate (PIP₂) binds to and directly agonizes Inward rectifying potassium channels(K_ir).^[19] PIP₂ is a plasma membrane lipid and its definitive role in gating ion channels was only recently demonstrated by X-ray crystallography.

Indirect modulation

In contrast to ligand-gated ion channels, there are also receptor systems in which the receptor and the ion channel are separate proteins in the cell membrane, instead of a single molecule. In this case, ion channels are indirectly modulated by activation of the receptor, instead of being gated directly.

G-protein-linked receptors

G-protein-coupled receptor mechanism

Also called G protein-coupled receptor, seven-transmembrane domain receptor, 7 TM receptor, constitute a large protein family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses. They pass through the cell membrane 7 times. G-protein-Linked receptors are a huge family that have hundreds of members identified. Ion channel linked receptors (e.g. GABAB, NMDA, etc.) are only a part of them.

Table 1. Three major families of Trimeric G Proteins^[20]

FAMILY	SOME FAMILY MEMBERS	ACTION MEDIATED BY	FUNCTIONS
I	GS	α	Activate adenylyl cyclase activates Ca2+ channels
	Golf	α	Activates adenylyl cyclase in olfactory sensory neurons
II	Gi	α	Inhibits adenylyl cyclase
		βɣ	Activates K+ channels
	G0	βɣ	Activates K+ channels; inactivate Ca2+ channels
		α and βɣ	Activates phospholipase C-β
	Gt (transducin)	α	Activate cyclic GMP phosphodiesterase in vertebrate rod photoreceptors
III	Gq	α	Activates phospholipase C-β

GABA_B receptor

GABAB receptors are metabotropic transmembrane receptors for gamma-aminobutyric acid. They are linked via G-proteins to K+ channels, when active, they create hyperpolarized effect and lower the potential inside the cell.^[21]

Ligands:

Agonists: GABA, Baclofen, gamma-Hydroxybutyrate, Phenibut etc.
Positive Allosteric Modulators: CGP-7930,^[22] Fendiline, BSPP, etc.
Antagonists:2-OH-saclofen, Saclofen, SCH-50911

Gα signaling

The cyclic-adenosine monophosphate (cAMP)-generating enzyme adenylate cyclase is the effector of both the G_αs and G_αi/o pathways. Ten different AC gene products in mammals, each with subtle differences in tissue distribution and/or function, all catalyze the conversion of cytosolic adenosine triphosphate (ATP) to cAMP, and all are directly stimulated by G-proteins of the G_αs class. Interaction with Gα subunits of the G_αi/o type, on the contrary, inhibits AC from generating cAMP. Thus, a GPCR coupled to G_αs counteracts the actions of a GPCR coupled to G_αi/o, and vice versa. The level of cytosolic cAMP may then determine the activity of various ion channels as well as members of the ser/thr-specific protein kinase A (PKA) family. As a result, cAMP is considered a second messenger and PKA a secondary effector.

The effector of the G_αq/11 pathway is phospholipase C-β (PLCβ), which catalyzes the cleavage of membrane-bound phosphatidylinositol 4,5-biphosphate (PIP2) into the second messengers inositol (1,4,5) trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on IP3 receptors found in the membrane of the endoplasmic reticulum (ER) to elicit Ca²⁺ release from the ER, DAG diffuses along the plasma membrane where it may activate any membrane localized forms of a second ser/thr kinase called protein kinase C (PKC). Since many isoforms of PKC are also activated by increases in intracellular Ca²⁺, both these pathways can also converge on each other to signal through the same secondary effector. Elevated intracellular Ca²⁺ also binds and allosterically activates proteins called calmodulins, which in turn go on to bind and allosterically activate enzymes such as Ca²⁺/calmodulin-dependent kinases (CAMKs).

The effectors of the G_α12/13 pathway are three RhoGEFs (p115-RhoGEF, PDZ-RhoGEF, and LARG), which, when bound to G_α12/13 allosterically activate the cytosolic small GTPase, Rho. Once bound to GTP, Rho can then go on to activate various proteins responsible for cytoskeleton regulation such as Rho-kinase (ROCK). Most GPCRs that couple to G_α12/13 also couple to other sub-classes, often G_αq/11.

Gβγ signaling

The above descriptions ignore the effects of Gβγ–signalling, which can also be important, in particular in the case of activated G_αi/o-coupled GPCRs. The primary effectors of Gβγ are various ion channels, such as G-protein-regulated inwardly rectifying K⁺ channels (GIRKs), P/Q- and N-type voltage-gated Ca²⁺ channels, as well as some isoforms of AC and PLC, along with some phosphoinositide-3-kinase (PI3K) isoforms.

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.^[23]^[24] In particular, the GABA and NMDA receptors are affected by anaesthetic agents at concentrations similar to those used in clinical anaesthesia.^[25]

By understanding the mechanism and exploring the chemical/biological/physical component that could function on those receptors, more and more clinical applications are proven by preliminary experiments or FDA.

Addiction treatment:

A series recent study shows that GABA receptors are involved with addiction-related behaviors, such as cocaine,^[26] heroin, alcohol,^[27] etc. Understanding the mechanism of receptors helped scientist develop pharmaceutical tools to treat addictions by modifying the receptors' activity.^[28]^[29]

Memantine

Memantine is approved by the U.S. F.D.A and the European Medicines Agency for the treatment of moderate-to-severe Alzheimer's disease,^[30] and has now received a limited recommendation by the UK's National Institute for Health and Care Excellence for patients who fail other treatment options.^[31]

Antidepressant treatment

Agomelatine, is a type of drug that acts on a dual melatonergic-serotonergic pathway, which have shown its efficacy in the treatment of anxious depression during clinical trails,^[32]^[33] study also suggests the efficacy in the treatment of atypical and melancholic depression.^[34]

References

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↑ Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 17 December 2013.
↑ Gonzalez, R; Chávez-Pascacio, K; Meneses, A (2013). "Role of 5-HT5A receptors in the consolidation of memory". Behavioural Brain Research. 252: 246–251. PMID 23735322. doi:10.1016/j.bbr.2013.05.051.
↑ Sawin, ER; Ranganathan, R; Horvitz, HR; Ranganathan; Horvitz (2000). "C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway". Neuron. 26 (3): 619–31. PMID 10896158. doi:10.1016/s0896-6273(00)81199-x.
↑ Hansen SB, Tao X, MacKinnon R (September 2011). "Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2". Nature. 477 (7365): 495–8. Bibcode:2011Natur.477..495H. PMC 3324908 . PMID 21874019. doi:10.1038/nature10370.
↑ Lodish, Harvey. Molecular cell biology. Macmillan, 2008.
↑ Chen, K; Li, HZ; Ye, N; Zhang, J; Wang, JJ (2005). "Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro". Brain Res Bull. 67 (4): 310–8. PMID 16182939. doi:10.1016/j.brainresbull.2005.07.004.
↑ Urwyler, S; Mosbacher, J; Lingenhoehl, K; Heid, J; Hofstetter, K; Froestl, W; Bettler, B; Kaupmann, K (2001). "Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501". Mol. Pharmacol. 60 (5): 963–71. PMID 11641424.
↑ Krasowski MD, Harrison NL (1999). "General anaesthetic actions on ligand-gated ion channels". Cell. Mol. Life Sci. 55 (10): 1278–303. PMC 2854026 . PMID 10487207. doi:10.1007/s000180050371.
↑ Dilger JP (2002). "The effects of general anaesthetics on ligand-gated ion channels". Br J Anaesth. 89 (1): 41–51. PMID 12173240. doi:10.1093/bja/aef161.
↑ 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.
↑ Goeders, N. E.; McNulty, M. A.; Mirkis, S.; McAllister, K. H. (1989). "Chlordiazepoxide alters intravenous cocaine self-administration in rats". Pharmacology, Biochemistry and Behavior. 33: 859–866. doi:10.1016/0091-3057(89)90483-8.
↑ Colombo, Giancarlo; et al. (2004). "Role of GABAB receptor in alcohol dependence: reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics". Neurotoxicity research. 6 (5): 403–414. doi:10.1007/BF03033315.
↑ Brebner, Karen, Anna Rose Childress, and David CS Roberts. "A potential role for GABAB agonists in the treatment of psychostimulant addiction." Alcohol and Alcoholism 37.5 (2002): 478-484. alcalc.oxfordjournals.org/content/37/5/478.short
↑ Young, Kimberly A.; et al. (2014). "Baclofen, a GABA B Agonist, reduces risk-taking and reveals the relationship between brain responses to drug cues and risk-taking in cocaine-addicted patients". Drug & Alcohol Dependence. 140: e247. doi:10.1016/j.drugalcdep.2014.02.684.
↑ Mount C, Downton C (July 2006). "Alzheimer disease: progress or profit?". Nat Med. 12 (7): 780–4. PMID 16829947. doi:10.1038/nm0706-780.
↑ NICE technology appraisal January 18, 2011 Azheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination
↑ Heun, R; Coral, RM; Ahokas, A; Nicolini, H; Teixeira, JM; Dehelean, P (2013). "1643 – Efficacy of agomelatine in more anxious elderly depressed patients. A randomized, double-blind study vs placebo". European Psychiatry. 28 (Suppl 1): 1. doi:10.1016/S0924-9338(13)76634-3.
↑ Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
↑ Avedisova, A; Marachev, M (2013). "2639 – The effectiveness of agomelatine (valdoxan) in the treatment of atypical depression". European Psychiatry. 28 (Suppl 1): 1. doi:10.1016/S0924-9338(13)77272-9.

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.esf.edu/efb/course/EFB325/lectures/29HormoneSignals.htm
http://www.genenames.org/

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Membrane transport protein: ion channels (TC 1A)

Ca²⁺: Calcium channel

Ligand-gated	Inositol trisphosphate receptor 1 2 3 Ryanodine receptor 1 2 3
Voltage-gated	L-type/Ca_vα 1.1 1.2 1.3 1.4 N-type/Ca_vα2.2 P-type/Ca_vα 2.1 Q-type/Ca_vα2.1 R-type/Ca_vα2.3 T-type/Ca_vα 3.1 3.2 3.3 α₂δ-subunits 1 2 β-subunits β1 β2 β3 β4 γ-subunits γ1 γ2 γ3 γ4 Cation channels of sperm 1 2 3 4 Two-pore channel 1 2

Na⁺: Sodium channel

Constitutively active	Epithelial sodium channel α β γ δ
Proton-gated	Amiloride-sensitive cation channel 1 2 3 4
Voltage-gated	Na_vα 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 7A Na_vβ 1 2 3 4

K⁺: Potassium channel

Calcium-activated	BK channel α1 β1 β2 β3 β4 SK channel SK1 SK2 SK3 IK channel IK1 K_Ca 1.1 2.1 2.2 2.3 3.1 4.1 4.2 5.1
Inward-rectifier	K_ATP K_ir 1.1 2.1 2.2 2.3 2.4 2.6 GIRK/K_ir 3.1 3.2 3.3 3.4 K_ir 4.1 4.2 5.1 6.1 6.2 7.1
Tandem pore domain	K2P 1 2 3 4 5 6 7 9 10 12 13 15 16 17 18
Voltage-gated	K_vα1-6 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 2.1 2.2 3.1 3.2 3.3 3.4 4.1 4.2 4.3 5.1 6.1 6.2 6.3 6.4 K_vα7-12 7.1 7.2 7.3 7.4 7.5 8.1 8.2 9.1 9.2 9.3 10.1 10.2 11.1/hERG 11.2 11.3 12.1 12.2 12.3 K_vβ 1 2 3 KCNIP 1 2 3 4 minK/ISK minK/ISK-like MiRP 1 2 3 Shaker gene

Miscellaneous

Cl⁻: Chloride channel	Calcium-activated chloride channels Anoctamin ANO1 Bestrophin 1 2 Chloride Channel Accessory 1 2 3 4 CFTR CLCN 1 2 3 4 5 6 7 KA KB CLIC 1 2 3 4 5 6 L1 CLNS 1A 1B
H⁺: Proton channel	HVCN1
M⁺: CNG cation channel	α 1 2 3 4 β 1 2 3 HCN FC 1 2 3 4
M⁺: TRP cation channel	TRPA (1) TRPC 1 2 3 4 4AP 5 6 7 TRPM 1 2 3 4 5 6 7 8 TRPML 1 2 3 TRPN TRPP 1 2 TRPV 1 2 3 4 5 6
H₂O (+ solutes): Porin	Aquaporin 0 1 2 3 4 5 6 7 8 9 Voltage-dependent anion channel 1 2 3 General bacterial porin family
Cytoplasm: Gap junction	Connexin A GJA1 GJA3 GJA4 GJA5 GJA8 GJA9 GJA10 B GJB1 GJB2 GJB3 GJB4 GJB5 GJB6 GJB7 C GJC1 GJC2 GJC3 D GJD2 GJD3 GJD4 Innexin

By gating mechanism

Ion channel class	Ligand-gated Light-gated Voltage-gated Stretch-activated

see also disorders

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