MECHANISM OF ACTION OF HORMONES

The hormone is “substances released from

ductless or endocrine glands directly to the

blood”.

A more modern definition of a hormone is

that it is synthesized by one type of cells &

transported through blood to act on another

type of cells.

Signal Transduction through G protein:

Action is through G protein coupled

receptors (GPCR).

Action of several hormones is effected

through this mechanism.

The GPCRs are transmembrane proteins with

7 helical segments spanning the membrane.

When any ligand binds, GPCRs activate heterotrimeric

GTP binding regulatory proteins (G-proteins).

The G-protein will interact with effector proteins

which may be enzymes or ion channel proteins, which

result in the desired effect.

Different types of G proteins are present in the cells

that are coupled with different receptors & activating

different effector proteins.

The extracellular messenger, the hormone (H)

combines with the specific receptor (R) on the

plasma membrane.

The H-R complex activates the regulatory

component of the protein designated as G-protein or

nucleotide regulatory protein.

G proteins – they can bind GTP & GDP.

The G-protein is a membrane protein consisting of α,

β and γ subunits.

When the hormone receptor complex is formed, the

activated receptor stimulates the G protein, which

carries the excitation signal to adenylate cyclase.

The hormone is not passed through the membrane; but

only the signal is passed; hence this mechanism is

called signal transduction.

The adenyl cyclase is embedded in the plasma

membrane.

When activated, GTP binds & β-γ subunits dissociate

from the α subunit.

Adenylate cyclase is activated by Gα – GTP.

The binding of hormone to the receptor triggers a

configurational change in the G protein which induces

the release of bound GDP & allows GTP to bind.

The hormone has an amplified response, since several

molecules of Gα – GTP are formed.

The active Gα – GTP is immediately inactivated by

GTPase.

The Gα – GDP form is inactive.

The activation is switched off when the GTP is

hydrolysed to GDP by the GTPase activity of the α

subunit.

The α subunit, which is bound to GDP, can re-

associate with β and γ subunits.

The GTP-GDP exchange rate decides the activity of

adenyl cyclase.

Adenyl cyclase or adenylate cyclase converts

ATP to cAMP (3',5'-cyclic AMP) &

phosphodiesterase hydrolyses cAMP to 5' AMP.

Cyclic AMP is a second messenger produced in

the cell in response to activation of adenylate

cyclase by active G protein.

During hormonal stimulation, cyclic AMP level

in the cell increases several times.

Acts as second messenger in the cell.

Regulates glycogen metabolism – increased

cAMP produces breakdown of glycogen

(glycogenolysis).

Regulates TGL metabolism – increased cAMP

produces lipolysis (breakdown of TGL).

cAMP stimulates protein kinases.

cAMP modulates transcription & translation.

cAMP involved in steroid biosynthesis.

cAMP regulates permeability of cell

membranes to water, Na+, K+ & calcium.

Involved in regulation insulin secretion,

catecholamine & melatonin synthesis.

Histamine increases cAMP, which increases

gastric secretion.

cGMP involved in phosphorylation of

proteins. E.g. acetyl choline in smooth muscle.

Role in vasodilation:

Nitroglycerine, cerine, sodium nitrite etc.

causes smooth muscle relaxation &

vasodilation by increasing cGMP.

Role in action of neurotransmitters:

GABA has been claimed to change cGMP

levels in cerebral tissues.

Role in prostaglandin synthesis:

PG-F2 require cGMP for its action.

Role in insulin actions:

Insulin action in some tissues is mediated

through cGMP, which activates protein

kinases.

Role in vasodilation produced by nitric oxide:

NO produces vasodilation & lowering BP by

increasing cGMP.

Calcium is intracellular regulator of cell

function.

Intracellular calcium level is low than

extracellular calcium.

3 types of calcium transport systems:

Voltage gated calcium channel.

Sodium/calcium antiport transporter.

Calcium transporting ATPase.

This type of signal transduction is

phospholipase C that hydrolyses

phosphatidyl inositol to 1,4,5-Inositol

triphosphate (IP3) & Diacyl Glycerol (DAG) that

act as second messengers.

PIP3 (Phosphatidyl Inositol 3,4,5- phosphate) is

another second messenger produced by the

action of a phosphoinositide kinase.

The phospholipase C may be activated either

by G proteins or calcium ions.

DAG can also be generated by the action of

phospholipase D that produces phosphatidic

acid which is hydrolyzed to DAG.

The steroid & thyroid hormones are included

in this group.

They diffuse through plasma membrane &

bind to the receptors in the cytoplasm.

The hormone receptor (HR) complex is

formed in the cytoplasm.

The complex is then translocated to the

nucleus.

Steroid hormone receptor proteins have a

molecular weight of about 80-100 kD.

Each monomer binds to a single steroid

molecule at a hydrophobic site, but on

binding to genes they dimerise.

The HR complex binds to HRE (hormone

responsive element).

HRE increase transcriptional activity.

Newly formed mRNA is translated to specific

protein, which brings metabolic effects.

Steroid hormones influence gene expression

& rate of transcription is also increased.

Textbook of Biochemistry – DM Vasudevan

Textbook of Biochemistry – U Satyanarayana

Textbook of Biochemistry – MN Chatterjea