This document discusses G protein-coupled receptors (GPCRs). It notes that GPCRs constitute the largest gene family in the human genome, with over 900 genes, and are the target of 40-50% of prescription drugs. The structure of GPCRs is described, including an extracellular region, 7 transmembrane regions, and intracellular region. The roles of GPCRs in immunity signaling and as the receptor for the bacterial peptide fMLP are also mentioned. Major mammalian GPCR subfamilies include rhodopsin-like, glucagon-like, and metabotropic glutamate receptor families.

1. In the name of god
G Protein - Coupled Receptors
by : Mahdi zarei
M.Sc. Student ,clinical biochemistry
Ferdowsi university of mashhad

2. G Protein - Coupled Receptors (GPCRs);
 GPCRs constitute the largest gene family in the human genome (~950 genes), ~500
of which are sensory.
Constitutes > 1% of the human genome.
 Comprises receptors for a diverse array of molecules: neurotransmitters, odorants,
lipids, neuropeptides, large glycoprotein hormones.
 They are the target of the majority of best-selling drugs (40%-50% of all prescription
pharmaceuticals on the market). Examples:
• Zyprexa (bipolar disorder & schizophrenia, Eli Lilly)
•Zantac (treat and prevent ulcers in the stomach and intestines; histamine receptor
antagonists, GlaxoSmithKline)

3. Molecular signatures of the GPCR fold ;
 The structure of a GPCR can be divided into three parts:
1 : the extra-cellular region, consisting of the N terminus and three
extracellular loops (ECL1–ECL3);
2 : the TM region, consisting of seven a-helices(TM1–TM7)
3 : the intracellular region, consisting of three intra-cellular loops (ICL1–ICL3), an
intracellular amphipathic helix (H8), and the C terminus .
 In a broad sense, the extracellular region modulates ligand access; the TMregion
forms the structural core, binds ligands and transduces this information to the
intracellular region through conformational changes, and the intracellular region
interfaces with cytosolic signalling proteins.

6. Structural and functional hub role of TM3.
AJ Venkatakrishnan et al. Nature 494, 185-194 (2013)
doi:10.1038/nature11896

7. Basic principle of GPCR-mediated signal transduction.
Vilardaga J et al. Molecular Endocrinology 2009;23:590-599
©2009 by Endocrine Society

8. Three Main Mammalian GPCR Subfamilies :
• Rhodopsin-like group – includes most of the GPCRs.(class
A GPCR)
• Glucagon-like group.(class B GPCR)
• Metabotropic glutamate (mGlu) and GABAB receptor
family.(class C GPCR)

9. GPCR Ligands
Rhodopsin family: amine receptors
Acetylcholine (muscarinic)
Adrenaline
Dopamine
Histamine
Serotonin
Octopamine
Trace amine
Rhodopsin family: peptide receptors
Angiotensin
Apelin
Bombesin
Bradykinin
C5a anaphylatoxin
CC Chemokine
CXC Chemokine
CX3C Chemokine
C Chemokine
Cholecystokinin
Endothelin
fMet-Leu-Phe
Galanin
Ghrelin
KiSS1-derived peptide
Melanocortin
Motilin
Neuromedin U
Neuropeptide FF
Neuropeptide S
Neuropeptide Y
Neuropeptide W / neuropeptide B
Neurotensin
Orexigenic neuropeptide QRFP
Opioid
Orexin
Oxytocin
Prokineticin
Somatostatin
Tachykinin
Urotensin II
Rhodopsin family: other receptors
Rhodopsin
Olfactory
Prostaglandin
Prostacyclin
Thromboxane
Adenosine
Purine / pyrimidine
Cannabinoid
Platelet activating factor
Gonadotropin-releasing hormone
Thyrotropin-releasing hormone
Melatonin
Lysosphingolipid and LPA (EDG)
Leukotriene B4 receptor
SREB
Mas proto-oncogene & Mas-related (MRGs)
RDC1
EBV-induced
Relaxin
LGR like
Free fatty acid
G protein-coupled bile acid
Nicotinic acid
GPR
GPR45 like
Cysteinyl leukotriene
Putative / unclassified Class A GPCRs
Secretin family
Calcitonin
Corticotropin releasing factor
Gastric inhibitory peptide
Glucagon
Growth hormone-releasing hormone
Parathyroid hormone
PACAP
Secretin
Vasoactive intestinal polypeptide
EMR1
Latrophilin
Brain-specific angiogenesis inhibitor (BAI)
Methuselah-like proteins (MTH)
Cadherin EGF LAG (CELSR)
Putative / unclassified Class B GPCRs
Metabotropic glutamate family
Glutamate (metabotropic)
Extracellular calcium-sensing
GABA-B
Pheromone (V2R)
Taste receptors (T1R)
Orphan GPRC5
Orphan GPCR6
Bride of sevenless proteins (BOSS)
Putative / unclassified Class C GPCRs
Other families
Frizzled / Smoothened family
Ocular albinism proteins
Vomeronasal receptors (V1R)
Taste receptors (T2R)
Insect odorant receptors
Nematode chemoreceptors
Plant Mlo receptors
Fungal pheromone
cAMP (Dictyostelium)
Bacterial rhodopsin

10. Class A Family:
 The class A GPCR family is referred to as the rhodopsin family. Class A
contains the largest number of members compiled into at least 19 subclasses
(subfamilies). Class A GPCRs include opsins, the vast majority of the odorant
receptors (at least 290 receptors), and receptors for monoamines, purines,
opioids, chemokines, some small peptide hormones, and the large
glycoprotein hormones that consist of thyroid stimulating hormone (TSH),
luteinizing hormone (LH), and follicle-stimulating hormone (FSH).

11. Receptor Family 1 – Rhodopsin Family
N
Y Y
C
C
TM7
TM6
TM5
TM4
TM3
TM2
TM1
Extracellular
Lipid Bilayer
CC
D
R
Y
Intracellular
C

12. Class B Family: secretin-like receptor class
 Structurally similar to that of Family 1, except that they have a much larger Nterminal domain, which contains multiple potential S-S bridges.
 Class B is comprised of 34 subclasses (subfamilies) and members include
receptors for peptide hormones or glycoprotein hormones, such as parathyroid
hormone (PTH), and calcitonin.
 The class B family also contains the vast majority of the orphan GPCRs.

13. Receptor Family 2 – Glucagon-like
Family
N
Y Y
C
C
TM7
TM6
TM5
TN4
TM3
TM2
TM1
Extracellular
Lipid Bilayer
CC
D
R
Y
Intracellular
C

14. Class C Family: mGluR/GABAB Family
 Extremely large extracellular N-terminal ligand binding domain.
 Shares only ~ 12 % sequence homology with that of Family 1, but the overall
transmembrane topology is similar.
 All Forms dimers ; Metabotropic glutamate receptors dimerization is stabelized by
disulfide bonds in the N-terminal extracellular domain.
 Class C is comprised of 8 subclasses (subfamilies) and members include the
metabotropic glutamate receptors (mGluR), extracellular Ca2+-sensing receptors,
taste receptors, and several odorant receptors, as well as the pheromone
receptors.

16. IMMUNITY SYSTEM SIGNALING
 Leukotrienes ,prostaglandins ,histamin ,c5a complement ,c3a
complement ,FMLP bacterial peptide and all chemokain use of
GPCR pathway.
 Members of this family are crucial to immune system function
because they also direct responses to anaphylatoxins such as
the complement fragment C5a and to many chemokines
(chemoattractant peptides and proteins), recruiting phagocytes to
sites of infection and promoting inflammation.

17. fMLP receptor
 The fMet-Leu-Phe (fMLP) receptor is a G-protein-coupled
receptor that senses the presence of bacteria by
recognizing a unique feature of bacte-rial polypeptides.
Protein synthesis in bacteria is typically initiated with an
N-formylmethionine (fMet) residue, an amino acid present
in prokaryotes but not in eukaryotes.