Signal Transduction

Definition of transduction

            At the cellular level, movement of a signals from out side into inside of a cell

 

Consists of two phrases,

1.    Intercellular transduction

2.    Intracellular transduction

 

Mechanism of signal transduction

·       Simple mechanisms

-        Receptors that have channels which upon ligand interaction allow signal to be passed in the form of small ion movements either into or out of the cell

 

·       Complex mechanisms

-        Coupling of ligands – receptor interactions to many intracellular events. Result in alteration of cellular activity/ changes in the programs of gene expression within cell.

Receptor

·       Any molecule that can bind to a bioactive substance/molecule including hormones and drugs (ligand)

·       Many types can be present,

-        In phospholipid bilayer

-        Cytosol

-        Nucleus

-        Various receptors for drugs

Ligand (Hormones) – 1^st messenger

·       Molecules integrating activities of multicellular organisms by endocrine signaling

·       Produced by specific glands

·       Secreted to blood

·       Act on target tissues

·       Chemical nature of hormones can be varied,

-        Amino acids

-        Peptides

-        Steroids

Second messengers

 

·       Binding of a hormone to a receptor initiates series of actions which leads to generation of second messengers within cells

·       Second messengers then trigger a series of molecular interactions that alter the physiological state of cell

·       This entire process is known as “signal transduction”.

Example – cyclic AMP, Inocitol triphosphate, DAG

·       Multiple hormones can utilize the same second messenger and a single hormone can utilize the more than one second messengers

 

Characteristics of signal transduction

·       Specificity

·       Amplification

·       Desensitization

·       Integration

Classification of signal transduction receptors

·      Transmembrane receptors: penetrate the plasma membrane, have the intrinsic enzymatic activity

example – Tyrosine Kinase (insulin receptors)

                     Tyrosine phosphate

                      Guanylate cyclase  

 

·       Receptors that are coupled inside the cell to GTP binding and hydrolyzing protein (G proteins) (Guanosine nucleotide binding protein)

Example – some hormone receptors (glucagon, angiotensin, vasopressin)

·       Intracellular: found intracellularly, upon ligand binding migrate to the nucleus where the ligand receptor complex directly arrect gene transcription

Example – Steroid hormones

 

Mechanisms of action of receptors

 

Transmembrane receptors

·       Capable of autophosphorylation and phosphorylation of other substrate

·       RTK receptors (Receptor Tyrosine Kinase) contains 4 major domains

1.    Extracellular ligand binding domain

2.    Intracellular tyrosine kinase domain

3.    Intracellular regulatory domain

4.    Transmembrane domain

 

Tyrosine Kinase second messenger system

 

·       Insulin is a peptide hormone, its receptor is tyrosine kinase

·       Hormone binds to receptor domain exposed on the cell’s surface

·       This activated Kinase domain located in the cytoplasmic region of the receptor

·       The receptor phosphorylates (autophosphorylation) itself as part of kinase activation process

·       The activated receptor then phosphorylates variety of intracellular targets, many are enzymes that become activate or inactivate upon phosphorylation

·       Some of targets of receptor kinase are protein phosphatases which upon activation by receptor tyrosine kinase become competent to remove phosphates from other proteins and alter their activity

·       A small change due to hormone binding Is amplified into a multitude of effects within the cell

·        

 

 Fate of the hormone receptor complex

 

·      Negative regulation of hormone action to internalize cell surface receptors

·      Internalization is stimulated by hormone binding

·      The resulting endosomes,

a.    may fuse with lysosomes leading to destruction of receptor and hormone

b.   hormone dissociated and the receptor is recycled by fusion of the endosome back into the plasma membrane

 

G proteins coupled receptors – peptide hormones

·       hormone binds surface receptor on target cells

·       binding hormone on the receptor causes in conformational change in G proteins

·       activates G proteins – has 3 sub units – Alpha , Beta , Gama and GDP binds to alpha sub unit

·       then GDP on alpha is replaced by GTP

·       Alpha + GTP dissociate from Gamma and Beta complex

·       Alpha – GTP complex binds adenylate cyclase on the membrane and activates

·       Adenylate cyclase catalyzes synthesis of 2^nd messenger cAMP in cytosol

 

cAMP binds protein kinase which catalases phosphorylation of various cellular proteins which in turns alter cellular activity

Second messenger

·       Binding of a hormone to a specific receptor on outer surface of the cell, activates adenylate cyclase that catalyzes formation of cAMP of the cell

·       cAMP binds cAMP dependent protein kinase which brings about phosphorylation of another protein

GTPase activity of alpha sub unit hydrolyses GDP + Pi

Presence of alpha subunit causes it to reassociate with Beta and Gamma complex

No more stimuli for adenylate cyclase to synthesize cAMP

cAMP already formed by hydrolyzed

second messenger causes either increase or decrease in the enzyme activity by cascade