CELL SIGNALLING

(For Year-I MBBS Students, 2018)

Dr Subir Gupta
Lecturer in Physiology
Faculty of Medical Sciences
University of West Indies
Cave Hill Campus, Barbados

 LEARNING OBJECTIVES
At the end of the class, students should be able to
understand
Ÿ Local and distant pathways by which cells communicate
with each other
Ÿ Receptors and their classification
Ÿ G protein coupled receptors and their role in the
process of signal transduction
Ÿ The concept of second messenger system
Ÿ Signal transduction by cytosolic and nuclear receptors
Ÿ Agonists and antagonists and how they modulate
transduction
Ÿ Up- and down-regulation of receptors and their
correlation with enhancement or suppression of cell
transduction


CELL-TO-CELL COMMUNICATION
 PATHWAYS OF CELL-TO-CELL COMMUNICATION

(A) Local pathways

►Through gap junctions
►Paracrine agents
● Cytokines
● Neurotransmitters

(B) Distant pathways

►Hormones
►Neurohormones
(A) Local pathways


(B) Distant pathways



SIGNAL TRANSDUCTION
 SIGNAL TRANSDUCTION TAKES PLACE
THROUGH RECEPTORS


►A cell may receive numerous chemicals (or
signals), however, responds to those chemicals for
which it has receptors

►A signaling molecule initiates its biologic effect by

binding to its specific receptor on/in a cell

►All the receptors are protein in nature

►Receptors are located in the cell membrane,

cytosol, or in the nucleus.


PATHWAYS OF SIGNAL TRANSDUCTION

(A) Through membrane receptors
(1) G protein-coupled receptors (GPCRs)
(2) Ligand-gated receptors
(3) Catalytic receptors (or receptor enzymes)

(B) Through intracellular receptors

 (1) SIGNAL TRANSDUCTION BY GPCR

►Characteristics of GPCRs
● Large transmembrane proteins
● Each GPCR has 7 membrane-spanning segments
● Have more than 1000 forms in various mammalian
tissues

►Characteristics of G proteins
● Located on cell membrane surface
● Are heterotrimers, i.e., consist of 3 different subunits-
α, β, and γ
● Each subunit exists in different forms


►Mechanism of signal transduction by GPCR

►Various second-messengers involved in the GPCR
pathway

■ Cyclic AMP (cAMP)

■ Inositol triphosphate (IP3) and diacylglycerol (DAG)
■ Arachidonic acid metabolites
● Thromboxanes
● Prostaglandins
● Prostacyclin
● Leucotrienes
(a) cAMP as a second-messenger

(b) IP3 and DAG as second-messengers

(c) Arachidonic acid metabolites as second-messengers

 (2) SIGNAL TRANSDUCTION BY LIGAND-GATED
RECEPTORS

►Nature of ligand-gated receptors
■ Transmembrane proteins
■ Each receptor, usually, has 5 subunits
■ Each receptor forms a channel after binding
with the ligand(s)



► Mechanism of signal transduction by ligand-gated
receptors

 (3) SIGNAL TRANSDUCTION BY CATALYTIC
RECEPTORS
Catalytic receptors are 3 major types:

(1) Receptor guanylyl cyclases (e.g., ANP receptor)–

Catalyze the generation of cGMP from GTP.

(2) Receptor tyrosine kinase receptor (e.g., Insulin

receptor)–
Phosphorylate tyrosine residues on themselves
and other proteins.

(3) Tyrosine kinase-associated receptors (e.g., Growth

hormone receptor)–
Interact with cytosolic (i.e., non-membrane
bound) tyrosine kinases.

►Characteristics of tyrosine kinase receptors
►Signal transduction by tyrosine kinase receptors

► Signal transduction by guanylyl cyclase receptor

► Signal transduction by tyrosine kinase-associated
receptors

 SIGNAL TRANSDUCTION BY CYTOSOLIC
RECEPTORS

 SIGNAL TRANSDUCTION BY NUCLEAR
RECEPTORS

 MODULATION OF SIGNAL PATHWAYS

►Specificity of receptors
● Multiple ligands for
one receptors
● Multiple receptors for
one ligand

►Agonists and antagonists

►Up- and down-regulation of receptors


►Termination of signal pathways

■ Removal of Ca++ from the cytosol into the ER or ECF.

■ The extracellular first messenger can be degraded by

enzymes in the extracellular space.

■ Many first messengers can be removed from the ECF

by transporting them into the neighboring cells.

■ Endocytosis of the entire receptor-ligand complex.