Knowledge of receptor with structure and mechanism

1. 1
Glycine Receptor
 INTRODUCTION
 Glycine is a simplest amino acid which is semi-
essential amino acid and it should be taken as a
nutritional supplement.
 Glycine is also a major inhibitory neurotransmitter in
the adult vertebrate central nervous system (CNS).
 Glycinergic synapses are particularly abundant in
spinal cord and brain stem, but are also found in
higher brain regions including the hippocampus.
 Glycine receptor (GlyR) is a member of the nicotinicoid
receptor superfamily.
 It is also known as an Inhibitory Chloride channel
protein.
 SYNTHESIS

2. 2
 STRUCTURE
 Glycine receptors exist as pentameric proteins, homo-
oligomers of the α isoforms (α1, α2, α3 or α4) or
hetero-oligomers which also contain the β-subtype
variant (β1) which is essential for targeting the
receptor to the synapse.
 Receptors are arranged as five subunits surrounding
a central pore, with each subunit composed of four α
helical transmembrane segments.
 There are presently four known isoforms of the α-
subunit (α1-4) of GlyR that are essential to
bind ligands (GLRA1, GLRA2, GLRA3, GLRA4) and a
single β-subunit (GLRB).
 The adult form of the GlyR is the heteromeric α1β
receptor, which is believed to have a stoichiometry
(proportion) of three α1 subunits and two β subunits
(3α : 2β) or four α1 subunits and one β subunit (4α
:1β).
 GlyR is also composed of Gephyrin together with α
and β subunits. Gephyrin is an enchoring protein
required for the postsynaptic clustering of GlyRs.

3. 3
 TYPES OF RECEPTOR
 The GLRA1 gene is located on chromosome 5p32. In
situ hybridisation studies have shown GLRA1 to be
expressed in the spinal cord, brain stem and colliculi.
GLRA1 trancripts together with GLRA3, predominate
in the postnatal CNS, replacing GLRA2, which is
more abundant in embryonic and neonatal neurones.
 The GLRA2 gene is located on chromosome Xp22.2-
22.1. GLRA2 is expressed in the hippocampus,
cerebral cortex and thalamus. GLRA2 trancripts
predominate in the neonatal and embyonic CNS,
decreases after birth and are replaced postnatally by
those of GLRA1 and to a lesser extent, GLRA3.
 The GLRA3 is expressed in the cerebellum, olfactory
bulb and hippocampus. GLRA3 trancripts, together
with GLRA1, predominate in the postnatal CNS,
replacing GLRA2, which is more abundant in
embryonic and neonatal neurones.
 The β-subnit reduces single channel conduction and
alters pharmacology and contributes to agonist
binding.
 MECHANISM
 Glycine is a major inhibitory neurotransmitter in the
adult CNS which acts by Ligand gated Ion Channel,
whereas it is excitatory during embryonic
development and around birth.
 This is due to a positive Chloride equilibrium
potential of the postsynaptic neurons, which results
in chloride efflux upon GlyR activation, causing
depolarisation.

4. 4
 In general, the chloride equilibrium potential shifts to
negative value owing to active chloride extrusion by
the K+ / Cl- co-transporter. Thus GlyR activation
becomes hyperpolarizing and therefore inhibitory.
 With regard to the source of energy, ion transporters
fall into two categories: primary active transporters
are directly fueled by ATP, while secondary active
transporters take the energy for transport of the
driven ion from the electrochemical gradient of
another ion species.
 The ubiquitous primary active transporter, the Na-K
ATPase, generates plasmalemmal K+ and Na+
gradients that provide the main source of energy for
most secondary active transporters.

5. 5
 Extrusion of Cl– via KCC mediated K-Clcotransport is
driven by the K+ gradient, while uptake of Cl– in many
neurons is driven by NKCC1 that exploits the
plasmalemmal Na+ gradient as its energy source for
Na-K-2Cl cotransport.
 The KCC2cotransporter operates at near-equilibrium,
which permits maximization of the efficiency of
harvesting energy from the K+ gradient to fuel the
extrusion of Cl–.
 The sodium-independent Cl- / HCO3- exchanger may
act as a significant Cl– uptake mechanism in
neurons. In addition to its role in neuronal Cl–
homeostasis, HCO3- acts as a significant carrier of
depolarizing current.
 FUNCTION
 To prevent tissue injury
 To enhance anti-oxidant capacity
 To promote protein synthesis and wound healing
 To improve immunity
 For biosynthesis of Heme, Creatinine & Glutathione
 REGULATION
 The GlyR beta subunit contains a putative tyrosine
phosphorylation site.
 Protein Tyrosine Kinase (PTK) regulate the function of
GlyRs on the tyrosine - 413 residue of the beta
subunit.

6. 6
 AGONIST
 Glycine : Endogenous glycine receptor agonist
 Taurine : Non-selective, endogenous glycine receptor
partial agonist
 β-Alanine : Endogenous glycine agonist, more
selective than taurine
 L-Alanine : Glycine receptor agonist
 Hypotaurine : Non-selective endogenous glycine
receptor agonist
 L-Serine : Weak endogenous glycine receptor agonist

7. 7
GLYCINE
Glycine is an amino acid, a building block for protein.
SOURCE :It is found primarily in gelatin and silk fibroin and
used therapeutically as a nutrient.
MECHANISM OF ACTION :In the CNS, there exist strychnine-
sensitive glycine binding sites as well as strychnine-
insensitive glycine binding sites. The strychnine-insensitive
glycine-binding site is located on the NMDA receptor
complex. The strychnine-sensitive glycine receptor complex
is comprised of a chloride channel and is a member of the
ligand-gated ion channel superfamily. The putative
antispastic activity of supplemental glycine could be
mediated by glycine's binding to strychnine-sensitive binding
sites in the spinal cord. This would result in increased
chloride conductance and consequent enhancement of
inhibitory neurotransmission. The ability of glycine to
potentiate NMDA receptor-mediated neurotransmission
raised the possibility of its use in the management of
neuroleptic-resistant negative symptoms in schizophrenia.
PHARMACOKINETIC :It is absorbed from small intestine via
an active transport mechanism and it is metabolized in liver.
USE :
 Glycine is used for treating schizophrenia, stroke,
benign prostatic hyperplasia (BPH), and some rare
inherited metabolic disorders.
 It is also used to protect kidneys from the harmful side
effects of certain drugs used after organ transplantation
as well as the liver from harmful effects of alcohol.
 Sometimes it can also be used to treat leg ulcers and
heal other wounds by applying on the skin.
 Glycine is also used as a sweetener, emollient,
emulsifying agent and solubilizing agent.

8. 8
 ANTAGONIST
 Selective
o Strychnine: toxic, colorless, bitter crystalline
alkaloid obtained from nux-vomica
o Brucine: closely related to strychnine, highly
toxic alkaloid present in nux-vomica
o Tutin: potent antagonist
 Non-selective
o Bicuculline: Phthalide-isoquinoline compound
o Caffeine: A crystalline compound found in tea
and coffee, a stimulant of CNS
o Picrotoxin: A bitter compound used to stimulate
the respiratory and nervous system
o Pitrazepin: Competitive glycine receptor
antagonist
 DISOREDERS
1. Hyperekplexia (Startle Disease)
 Hyperekplexia is a hereditary neuromotor disorder
resulting from the mutation of Glrα and Glrβ genes
cause an impairment of glycinergic transmission on
the chromosome 5q33 – q35
 It is characterised by an exaggerated startle reaction
in response to unexpected auditory or visual stimuli
often followed by a short period of generalised
stiffness.
 It is treated by administration of the drug
Clonazepam.

9. 9
2. Bovine Myoclonus
 A congential recessive startle syndrome is called
myoclonus.
 It is due to a deletion of single base pair in the α1
subunit gene, leading to a frameshift and a
premature stop codon.
 This mutation induces a dramatic reduction in the
surface expression of functional GlyR.
3. Non-ketoticHyperglycinemia
 Non-ketotichyperglycinemia is an autosomal disorder
caused by a defect in the enzyme system that breaks
down the amino acid glycine, resulting in an
accumulation of glycine in the body’s tissues and
fluids.
 It is caused by the genetic mutation in the genes that
encode the components of the glycine cleavage
enzyme system.
 The treatment involves : Sodium benzoate is used to
reduce serum glycine levels and Dextromethorphan is
used to reduce seizures and improve alertness.
4. Glycinuria
 Glycinuria is also an autosomal disorder resulting
from the impaired renal tubular reabsorption of
glycine.
 This will lead to increased excretion of glycine but
serum glycine level is normal leading to the increased
risk of oxalate stones.

10. 10
 REFERENCE
 http://physrev.physiology.org/content/84/4/1051.lo
ng
 http://www.ucl.ac.uk/pharmacology/dc-bits/c-and-
sivilotti-2004-tins.pdf
 https://www.researchgate.net/figure/24236782_fig1
_Figure-1-Ion-Transport-Mechanisms-Underlying-
GABA-A-and-Glycine-Receptor-Mediated
 https://www.tocris.com/pharmacologicalBrowser.ph
p?ItemId=4979#.WAfQe-B97IU
 http://www.sciencedirect.com/science/article/pii/S0
165614702021387
 https://www.researchgate.net/publication/8540234_
Function_and_structure_in_glycine_receptors_and_so
me_of_their_relatives
 http://dcscience.net/lewis98.pdf
 http://www.guiametabolica.org/sites/default/files/B
rochure_NonKetotic_Hyperglicemina_def.pdf
 http://www.drugbank.ca/drugs/DB00145