BPS/IUPHAR Guide to Pharmacology | GRAC IC FAMILIES

Glycine receptors

More information on this family may be found on the IUPHAR-DB family and introduction pages.

The inhibitory glycine receptor [nomenclature as agreed by the NC-IUPHAR sub-committee on glycine receptors] is a member of the Cys-loop superfamily of transmitter-gated ion channels that includes the GABA_A, nicotinic acetylcholine and 5-HT₃ receptors [16]. The receptor is expressed either as a homo-pentamer of a subunits, or a complex now thought to harbour 2α and 3β subunits [2,6], that contain an intrinsic anion channel. Four differentially expressed isoforms of the α-subunit (α1-α4) and one variant of the β-subunit (β1, ENSG00000109738) have been identified by genomic and cDNA cloning. Further diversity originates from alternative splicing of the primary gene transcripts for α1 (α1^INS and α1^del), α2 (α2A and α2B), α3 (α3S and α3L) and β (βΔ7) subunits and by mRNA editing of the α2 and α3 subunit [4,19,23]. Both α2 splicing and α3 mRNA editing can produce subunits (i.e., α2B and α3P185L) with enhanced agonist sensitivity. Predominantly, the mature form of the receptor contains α1 (or α3) and β subunits while the immature form is mostly composed of only α2 subunits. RNA transcripts encoding the α4-subunit have not been detected in adult humans. The N-terminal domain of the α-subunit contains both the agonist and strychnine binding sites that consist of several discontinuous regions of amino acids. Inclusion of the β-subunit in the pentameric glycine receptor contributes to agonist binding, reduces single channel conductance and alters pharmacology. The β-subunit also anchors the receptor, via an amphipathic sequence within the large intracellular loop region, to gephyrin. The latter is a cytoskeletal attachment protein that binds to a number of subsynaptic proteins involved in cytoskeletal structure and thus clusters and anchors hetero-oligomeric receptors to the synapse [11-12,21]. G-protein βγ subunits enhance the open state probability of native and recombinant glycine receptors by association with domains within the large intracellular loop [30-31]. Intracellular chloride concentration modulates the kinetics of native and recombinant glycine receptors [24]. Intracellular Ca²⁺ appears to increase native and recombinant glycine receptor affinity, prolonging channel open events, by a mechanism that does not involve phosphorylation [5].

Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Subunits

α1 Show »« Hide

Nomenclature

α1

Other names

STHE, glycine receptor, alpha 1 (startle disease/hyperekplexia), startle disease/hyperekplexia, stiff person syndrome, GLYRA1, glycine receptor 48 kDa subunit, glycine receptor strychnine-binding subunit, glycine receptor subunit alpha-1, glycine receptor, alpha 1, glycine receptor, alpha 1 subunit, ot, oscillator, nmf11, B230397M16Rik, spd

IUPHAR-DB

α1

Genes

GLRA1 (Hs), Glra1 (Mm), Glra1 (Rn)

Ensembl ID

ENSG00000145888 (Hs), ENSMUSG00000000263 (Mm), ENSRNOG00000013588 (Rn)

Selective agonists (potency order)

glycine > β-alanine > taurine

Selective antagonists
(IC₅₀)

HU-308 (weak inhibition)

PMBA

strychnine

pregnenolone sulphate (K_i 1.9x10^-6 M)

tropisetron (K_i 8.4x10^-5 M)

ginkgolide X (7.6x10^-7 M)

nifedipine (3.3x10^-6 M)

bilobalide (2x10^-5 M)

colchicine (3.24x10^-4 M)

Channel Blockers
(IC₅₀)

cyanotriphenylborate (1.3x10^-6 M)

ginkgolide B (6x10^-7 – 8x10^-6 M)

picrotin (5.2x10^-6 M)

picrotoxinin (5.1x10^-6 M)

picrotoxin (6.3x10^-6 M)

Endogenous allosteric regulators

H⁺ (extracellular) (Inhibition, endogenous)

Zn²⁺ (Potentiation, endogenous; not affected by β subunit co-expression) (EC₅₀ 3.7x10^-8 M)

Cu²⁺ (Inhibition, endogenous; not affected by β subunit co-expression) (IC₅₀ 4x10^-6 – 1.5x10^-5 M)

Zn²⁺ (Inhibition, endogenous) (IC₅₀ 1.5x10^-5 M)

Selective allosteric regulators

anandamide (Potentiation) (EC₅₀ 3.8x10^-8 M)

HU-210 (Potentiation) (EC₅₀ 2.7x10^-7 M)

Δ⁹-tetrahydrocannabinol (Potentiation, ~1500% potentiation) (EC₅₀ ~3x10^-6 M)

Radioligands
(K_d)

[³H]strychnine

Functional characteristics

γ = 86 pS (main state); (+ β = 44 pS)

α2 Show »« Hide

Nomenclature

α2

Other names

GLR, RNNEOGLY, Glycine receptor alpha 2 subunit (glycine receptor neonatal), Glycine receptor alpha 2 subunit (glycine receptor, neonatal), glycine receptor strychnine-binding subunit, glycine receptor subunit alpha-2, glycine receptor, alpha 2 subunit

IUPHAR-DB

α2

Genes

GLRA2 (Hs), Glra2 (Mm), Glra2 (Rn)

Ensembl ID

ENSG00000101958 (Hs), ENSMUSG00000018589 (Mm), ENSRNOG00000003313 (Rn)

Selective agonists (potency order)

glycine > β-alanine > taurine

Selective antagonists
(IC₅₀)

PMBA

strychnine

pregnenolone sulphate (K_i 5.5x10^-6 M)

tropisetron (K_i 1.3x10^-5 M)

HU-210 (9x10^-8 M)

WIN55212-2 (2.2x10^-7 M)

HU-308 (1.1x10^-6 M)

ginkgolide X (2.8x10^-6 M)

bilobalide (8x10^-6 M)

colchicine (6.4x10^-5 M)

5,7-dichlorokynurenic acid (1.88x10^-4 M)

Channel Blockers
(IC₅₀)

picrotoxinin (4.1x10^-7 M)

picrotoxin (2.3x10^-6 M)

ginkgolide B (3.7x10^-6 – 1.14x10^-5 M)

picrotin (1.31x10^-5 M)

cyanotriphenylborate (>2x10^-5 M)

Endogenous allosteric regulators

Zn²⁺ (Potentiation, endogenous; not affected by β subunit co-expression) (EC₅₀ 5.4x10^-7 M)

Cu²⁺ (Inhibition, endogenous) (IC₅₀ 1.7x10^-5 M)

Zn²⁺ (Inhibition, endogenous) (IC₅₀ 3.6x10^-4 M)

Selective allosteric regulators

Δ⁹-tetrahydrocannabinol (Potentiation, ~230% potentiation) (EC₅₀ ~1x10^-6 M)

Radioligands
(K_d)

[³H]strychnine

Functional characteristics

γ = 111 pS (main state); (+ β = 54 pS)

α3 Show »« Hide

Nomenclature

α3

Other names

glycine receptor subunit alpha-3, glycine receptor, alpha 3, glycine receptor, alpha 3 subunit

IUPHAR-DB

α3

Genes

GLRA3 (Hs), Glra3 (Mm), Glra3 (Rn)

Ensembl ID

ENSG00000145451 (Hs), ENSMUSG00000038257 (Mm)

Selective agonists (potency order)

glycine > β-alanine > taurine

Selective antagonists
(IC₅₀)

strychnine

HU-210 (5x10^-8 M)

HU-308 (9.7x10^-8 M)

WIN55212-2 (9.7x10^-8 M)

(12E,20Z,18S)-8-hydroxyvariabilin (7x10^-6 M)

nifedipine (2.92x10^-5 M)

Channel Blockers
(IC₅₀)

picrotoxin (block is weaker when β subunit is co-expressed)

picrotoxinin (4.3x10^-7 M)

ginkgolide B (1.8x10^-6 M)

picrotin (6x10^-6 M)

Endogenous allosteric regulators

Cu²⁺ (Inhibition, endogenous) (IC₅₀ 9x10^-6 M)

Zn²⁺ (Inhibition, endogenous) (IC₅₀ 1.5x10^-4 M)

Selective allosteric regulators

Δ⁹-tetrahydrocannabinol (Potentiation, ~1500% potentiation) (EC₅₀ ~5x10^-6 M)

Radioligands
(K_d)

[³H]strychnine

Functional characteristics

γ = 105 pS (main state); (+ β = 48)

α4 (pseudogene in humans) Show »« Hide

Nomenclature	α4 (pseudogene in humans)
Other names	LOC367912, RGD1564103, RGD1564103_predicted, glycine receptor subunit alpha-4, glycine receptor, alpha 4, glycine receptor, alpha 4 subunit, similar to Glycine receptor alpha-4 chain precursor, similar to Glycine receptor alpha-4 chain precursor (predicted)
IUPHAR-DB	α4 (pseudogene in humans)
Genes	GLRA4 (Hs), Glra4 (Mm), Glra4 (Rn)
Ensembl ID	ENSG00000188828 (Hs), ENSMUSG00000018595 (Mm), ENSRNOG00000002391 (Rn)

β Show »« Hide

Nomenclature

Other names

Glycine receptor beta, glycine receptor 58 kDa subunit, glycine receptor subunit beta, glycine receptor, beta, glycine receptor, beta subunit, AI853901, spa

IUPHAR-DB

Genes

GLRB (Hs), Glrb (Mm), Glrb (Rn)

Ensembl ID

ENSG00000109738 (Hs), ENSMUSG00000028020 (Mm), ENSRNOG00000010199 (Rn)

Selective antagonists
(IC₅₀)

pregnenolone sulphate (when co-expressed with the α1 subunit) (K_i 2.7x10^-6 M)

tropisetron (when co-expressed with the α2 subunit) (K_i 5.4x10^-6 M)

pregnenolone sulphate (when co-expressed with the α2 subunit) (K_i 1.01x10^-5 M)

nifedipine (when co-expressed with the α1 subunit) (1.2x10^-6 M)

nifedipine (when co-expressed with the α3 subunit) (1.14x10^-5 M)

bilobalide (when co-expressed with the α2 subunit) (5x10^-5 M)

bilobalide (when co-expressed with the α1 subunit) (2.04x10^-4 M)

ginkgolide X (when co-expressed with the α2 subunit) (>3x10^-4 M)

ginkgolide X (when co-expressed with the α1 subunit) (>3x10^-4 M)

Channel Blockers
(IC₅₀)

ginkgolide B (when co-expressed with the α2 subunit) (1.4x10^-7 – 8x10^-7 M)

ginkgolide B (when co-expressed with the α3 subunit) (5.5x10^-7 M)

ginkgolide B (when co-expressed with the α1 subunit) (1.8x10^-7 – 2.5x10^-6 M)

cyanotriphenylborate (when co-expressed with the α1 subunit) (2.8x10^-6 M)

cyanotriphenylborate (when co-expressed with the α1 subunit) (7.5x10^-6 M)

picrotoxinin (when co-expressed with the α3 subunit) (8.9x10^-6 M)

picrotin (when co-expressed with the α3 subunit) (2.4x10^-5 M)

picrotin (when co-expressed with the α1 subunit) (2.7x10^-5 M)

picrotoxinin (when co-expressed with the α1 subunit) (2.7x10^-5 M)

picrotoxin (when co-expressed with the α2 subunit) (2.97x10^-5 M)

picrotoxin (when co-expressed with the α1 subunit) (2.19x10^-4 M)

Endogenous allosteric regulators

Zn²⁺ (Inhibition, endogenous; when co-expressed with the α1 subunit) (IC₅₀ 1.3x10^-5 M)

Zn²⁺ (Inhibition, endogenous; when co-expressed with the α2 subunit) (IC₅₀ 1.8x10^-4 M)

Comment

Ligand interaction data for hetero-oligomer receptors containing the β subunit are also listed under the α subunit

Comments Show »« Hide

Data in the table refer to homo-oligomeric assemblies of the α-subunit, significant changes introduced by co-expression of the β1 subunit are indicated in parenthesis. Not all glycine receptor ligands are listed within the table, but some that may be useful in distinguishing between glycine receptor isoforms are indicated). pregnenolone sulphate, tropisetron and colchicine, for example, although not selective antagonists of glycine receptors, are included for this purpose. strychnine is a potent and selective competitive glycine receptor antagonist with affinities in the range 5–15 nM. RU5135 demonstrates comparable potency, but additionally blocks GABA_A receptors. There are conflicting reports concerning the ability of cannabinoids to inhibit [14], or potentiate and at high concentrations activate [1,3,7,26-27] glycine receptors. Nonetheless, cannabinoid analogues may hold promise in distinguishing between glycine receptor subtypes [27]. In addition, potentiation of glycine receptor activity by cannabinoids has been claimed to contribute to cannabis-induced analgesia relying on Ser296/307 (α1/α3) in M3 [26]. Several analogues of muscimol and piperidine act as agonists and antagonists of both glycine and GABA_Areceptors. picrotoxin acts as an allosteric inhibitor that appears to bind within the pore, and shows strong selectivity towards homomeric receptors. While its components, picrotoxinin and picrotin, have equal potencies at a1 receptors, their potencies at α2 and α3 receptors differ modestly and may allow some distinction between different receptor types [28]. Binding of picrotoxin within the pore has recently been demonstrated in the crystal structure of the related C. elegans GluCl Cys-loop receptor [8]. In addition to the compounds listed in the table, numerous agents act as allosteric regulators of glycine receptors (comprehensively reviewed in [13,15,25,32]). Zn²+ acts through distinct binding sites of high- and low-affinity to allosterically enhance channel function at low (<10 µM) concentrations and inhibits responses at higher concentrations in a subunit selective manner [20]. The effect of Zn²⁺ is somewhat mimicked by Ni²⁺. Endogenous Zn²⁺ is essential for normal glycinergic neurotransmission mediated by α1 subunit-containing receptors [9]. Elevation of intracellular Ca²⁺ produces fast potentiation of glycine receptor-mediated responses. Dideoxyforskolin (4 µM) and tamoxifen (0.2–5 µM) both potentiate responses to low glycine concentrations (15 µM), but act as inhibitors at higher glycine concentrations (100 µM). Additional modulatory agents that enhance glycine receptor function include inhalational, and several intravenous general anaesthetics (e.g. minaxolone, propofol and pentobarbitone) and certain neurosteroids. ethanol and higher order n-alcohols also enhance glycine receptor function although whether this occurs by a direct allosteric action at the receptor [18], or through G-protein βγ subunits [29] is debated. Recent crystal structures of the bacterial homologue, GLIC, have identified transmembrane binding pockets for both anaesthetics [22] and alcohols [10]. Solvents inhaled as drugs of abuse (e.g. toluene, 1-1-1-trichloroethane) may act at sites that overlap with those recognising alcohols and volatile anaesthetics to produce potentiation of glycine receptor function. The function of glycine receptors formed as homomeric complexes of α1 or α2 subunits, or hetero-oligomers of α1/β or α2/β subunits, is differentially affected by the 5-HT₃ receptor antagonist tropisetron (ICS 205-930) which may evoke potentiation (which may occur within the femtomolar range at the homomeric glycine α1 receptor), or inhibition, depending upon the subunit composition of the receptor and the concentrations of the modulator and glycine employed. Potentiation and inhibition by tropeines involves different binding modes [17]. Additional tropeines, including atropine, modulate glycine receptor activity.