Receptors 2

Dr Manjuprasad

Moderator: Dr Vijayalaxmi M.K

They are the molecules which relay signals

from receptors on cell surface to target

molecules inside the cytoplasm or nucleus.

Discovered by Earl Wilbur Sutherland in 1971

Types:

• Hydrophobic: eg; DAG, phosphotidyl inositol

• Hydrophilic: eg; cAMP, cGMP, IP3 & calcium

• Gases : eg; NO, CO, H2S

Synthesized, released & broken down again

in specific reactions by enzymes.

Can be stored & quickly released when

needed

Production, release and destruction can be

localised

Cyclic nucleotides: cAMP

cGMP

Calcium

Lipid derivatives: IP3

DAG

cAMP Synthesized from ATP

Regulates some ion channels as ligands

Regulates kinase

which phosphorylates substrates

- increases glycogen breakdown

- decrease glycogen synthesis

-increase cardiac beat strength

Eg: Adrenaline, Glucagon, LH

cGMP Made from GTP

Membrane bound or soluble

Can act as a receptor

Regulates some ion channels and protein kinases

Important in smooth muscle relaxation and visual

system

Eg: ANP, NO

Calcium:

At rest maintains low cytoplasmic

concentration

Channels open with ligand gated or voltage

gateing

Actions: muscle contraction

neuronal transmission

cellular motility

cell growth

Inositol tri-phosphate

Hydrophilic

Agonist for internal calcium channel

[Ca++]i rises

Multiple effects through Ca++-binding

proteins

Diacylglycerol

Hydrophobic

Targets PKC (a kinase)

PKC requires Ca++ and DAG

Types:

• Voltage gated

eg: Lignocaine, verapamil

• Ligand gated

eg: gabapentine, nicotine

Multiple isoforms

Generation of action potential

Sodium channels

One α and 2β

α subunit has 4 domains- sodium ion

selective pore forming pseudo tetramer

Β subunit span the membrane once

Each domain has 6 membrane spanning helices (S1-S6)

Extracellular loop S5 & S6 or pore forming loop dips back into the pore

Provides selective filter for sodium ions

S4 of each domain surrounding the pore contain charged amino acids that forms the voltage sensor

Cause conformational change in pore at more positive voltage leading to opening of pore

Calcium channel

This has a large α subunit (4 domains & 6

membrane spanning helices),

3 regulatory subunits ie β,δ and γ

Types:

L-Type- long lasting

found in Skeletal muscle, smooth muscle, bone,

cardiac myosites and dendrites

P-type (purkinje)

Purkinje neurons in the cerebellum / Cerebellar

granule cells

N-type (neuronal)

Throughout the brain and peripheral nervous system

R-type (residual)

Cerebellar granule cells, other neurons

T-type (transient)

neurons, cells that have pacemaker activity, bone

(osteocytes)

Potassium channels:

form channels as tetramers

4 membrane spanning domains

2 pore domain or leak potassium channels

-Dimers having 4 membrane spanning domains

surrounding 2 P loops

-Voltage insensitive

-Regulated by G proteins and H ions

• Activated by binding of ligand to a specific site

which causes conformational change in the

channel

• Specialized ion channels that are activated by

intracellular small molecules

Belong to Kv family

Eg:-cyclic nucleotide gated channel

-IP3 sensitive Ca channels

-5HT3 regulated channels

Large proteins consisting of a single chain upto

1000 residues with single membrane spanning

helix

Important role in-cell division

-growth

-differentiation

-inflammation

-tissue repair

-apoptosis

-immune response

Receptor tyrosine kinases

Serine/ threonine kinases

Cytokine receptors

Insulin, EGF, PDGF, NGF, FGF, VEGF

Have a single polypeptide chain except for insulin

receptor

Extracellular cysteine rich residues, short

transmembrane domain and intracellularly

containing one tyrosine kinase domains

lack intrinsic enzyme activity. When

occupied, they associate with, and activate,

a cytosolic tyrosine kinase, such as Jak (the

Janus kinase)

for these receptors include cytokines such as

interferons and colony-stimulating factors

involved in immunological responses.

Ligand binding -- dimerises

Phosphorylation of kinase domains

Activated receptor phosphorylates smad

Dissociation from receptor

Association with transcription factors and

gene regulation

There are also inhibitory smads

Compete with phosphorylated smads to terminate

signalling

( S6 & S7 )

Expressed in haematopoetic cells

Related to innate immunity

Structure is similar to kinase linked receptors

Ligands- peptidoglycans, lipopolysaccharides,

and viruses

Activation produces an inflammatory response

These are ligand activated transcription

factors that transduce signals by modifying a

gene transcription

Present in soluble phase become mobile in

presence of ligand and translocate from

cytoplasm to nucleus

RXR dwell mainly in nuclear compartment

Type 1:Receptors of steroid harmones

Eg: estrogen, progesterone, testosterone

Type 2:ligands present in cytoplasm to some

extent

Eg: PPAR-that recognises fatty acids

Type 3: characteristics of both 1 & 2

Imp role in endocrine signalling

Eg: thyroid harmone receptor, VitD receptor

Myasthenia Gravis

Testicular feminization syndrome

Cystic Fibrosis

SIDS

Lambert eaton syndrome

Goodman and Gilman – 12th edition

Rang and Dales pharmacology 7th edition

Textbook of medical pharmacology – Padmaja

udaykumar

Uptodate.com

Second messenger and signal transduction-

Dr Tim Bloom