Cell signalling and G-

protein linked receptors

 Cell signalling
The process in which cells sense the extracellular stimuli through
membranous or intracellular receptors, transduce the signals via
intracellular molecules, and thus regulate the biological function of
the cells
It always have a signal molecule - ligand and receptor molecule
cell surface or proteins in the cell
Cell signalling is specific

Binding is through weak non- covalent bonds

Sensitive due to 1) affinity

2) amplification

3) cooperativity
Signal molecules
Physical signals
Light, electronic, mechanic, UV, heat, volume or osmotic, etc

Chemical signals
Hormones, neurotransmitters, Growth factors, cytokines, odor molecules, ATP,
active oxygen, drugs, toxins, etc
Modes of cell-cell signaling

1. Direct cell-cell or cell-matrix (integrins and cadherins)

2. Indirect: Secreted molecules.

A. Endocrine signaling.
The signaling molecules are hormones secreted by endocrine cells and carried
through the circulation system to act on target cells at distant body sites.

B. Paracrine signaling. The signaling molecules released by one cell act on

neighboring target cells (neurotransmitters).

C. Autocrine signaling. Cells respond to signaling molecules that they themselves

produce (response of the immune system to foreign antigens,and cancer cells).
 The primary pathways of cell
signalling
G-protein-mediated pathway
Adenylate cyclase mediated pathway
Phospholipase mediated pathway
Small G-protein-mediated pathway

Non-G-protein-mediated pathway
Receptor tyrosine kinase mediated pathway
Receptor serine/threonine kinase mediated pathway
Receptor guanilate cyclase mediated pathway
Intracellular (unclear) receptor mediated pathway
 G-Protein Coupled Receptors
Largest family of cell surface receptors that bind to G protein
Sense moleculesoutside thecelland activate insidesignal
transductionpathways and, ultimately, cellular responses
found only ineukaryotes, includingyeast,choanoflagellates,and animals
involved in many diseases so target of approximately 40% of all modern
medicinal drugs

STRUCTURE:
GPCRs areintegral membrane proteinsthat possess seven membrane-
spanning domains ortransmembrane helices.
The extracellular parts of the receptor can beglycosylated.
These extracellular loops also contain two highly
conservedcysteineresidues that formdisulfide bondsto stabilize the
receptor structure
 G-protein coupled receptors
G-protein composed of one
alpha, beta, and gamma
subunit
2 primary signaling
cascades: cAMP or
phosphatidylinositol
pathways
Cell
membrane


Pathway activated depends
GDP
on alpha subunit type
(Gs, Gi/o, Gq/11,
G12/13)
PicScience GDP bound to when
G-protein coupled receptors
When a ligand binds, the receptor
changes conformation, allowing G-
protein to be activated (GDP is
exchanged for GTP)
G-protein dissociates from receptor
then subunits from each other.

Cell
membrane


GTP
GDP

GTP
 cAMP pathway
Gs binds to Adenylate Cyclase
(AC) and stimulates cAMP
synthesis from ATP
Gi/o binds to AC and inhibits
cAMP synthesis

AC Cell
membrane
cAMP

GTP
GDP
ATP
GTP
 Phosphatidylinositol
pathway
Gq/11 binds to Phospholipase C
(PLC) and catalyzes the cleavage of
phosphatidylinositol 4,5-
biphosphate (PIP2) into the second
messengers inositol (1,4,5)
trisphosphate (IP3) and
diacylglycerol (DAG).

PIP DAG
2
PLC P
P
IP3
GTP
GDP
P
GTP

To sarcoplasmic
 6 Major classes of these
Class A (or 1) (Rhodopsin-like)
Class B (or 2) (Secretin receptor family)
Class C (or 3) (Metabotropic glutamate/pheromone)
Class D (or 4) (Fungal mating pheromone receptors)
Class E (or 5) (Cyclic AMP receptors)
Class F (or 6) (Frizzled/Smoothened)