HormonesBio-signaling

Dr. Aga Syed SameerCSIR Lecturer (Demonstrator)Department of Biochemistry,Medical College,Sher-I-Kashmir Institute of Medical Sciences, Bemina, Srinagar, Kashmir, 190010. India.

First MBBS

Lecture No: H 01

Time : 10:00am

Dated: 05/03/2015

References:

1. Biochemistry – Lehninger’s, Nelson & Cox

2. Cell biology – Gerald Karp

3. Molecular Biology of Cell – Bruce Alberts’

Cellular Communication

• Cells usually communicate with each other through “Extracellular Messenger Molecules”

• Extracellular messengers can travel

• “Short distance” and “Stimulate” cells that are in close proximity to the origin of the message

• “Throughout the Body”, potentially stimulating cells that are far away from the source

Types

• Autocrine – cell elaborates a self-addressed message• Cells producing a messenger expresses receptors on its own surface

to respond to the messenger

• Paracrine – local communication mechanism• Messenger molecules travel only short distances through the

extracellular space to cell that are in close proximity of the secreting cell

• Juxtacrine – two cells - direct contact

• Endocrine – signal molecule →blood → target cell• Messenger molecules use the bloodstream for their transport from

the secreting cells to the target ones

Hormones• Organic substances that are produced and secreted

by “Endocrine glands” in minute quantity to regulate the various physiological and metabolic functions of body

• The action of hormones is regulated by many factors:

• Rate of secretion/synthesis in endocrine organs

• Specified transport system in plasma

• Hormone specific receptors in target cells/organs

• Rate/mechanism of degradation of hormoneswithin liver/kidneys

HormonesProperties Group I Group II

Types Steroids, Triiodothyroxine, Retinoids

Polypeptides, Proteins, Catecholamines

Solubility Lipophilic Hydrophilic

Transport Proteins

Yes No

Plasma Half Life Long (h→days) Short (min)

Receptor Intracellular Plasmamembrane

Mediator Hormone Receptor Complex

cAMP, cGMP, Ca2+, Kinasecacades

Polypeptides

Steroids

Amino acid derivatives

Insulin

glucagon

somatotropin

FSH

LH

vasopressin

Oxytocin

thyrotropin

ACTH

Estrogen

testosterone

cortisol

Aldosterone

corticosterone

Progesterone

Epinephrine

norepinephrine

dopamine

Thyroxine, T3 and T4

Melatonin

Serotonin

Hormones

Hormones

Substances that fool the responder into

thinking a hormone has bound are call agonists

Substances that prevent the binding of the

natural hormone and do not elicit a response from

the receptor are called antagonists

Receptors: Specialized glycoproteins which are expressed on the surface of target cells with which hormone interacts to mediate its action

Ligands: A substance which can combine with the receptor to form ligand- receptor complex and in-turn evokes cellular response

All hormones interact with target cells by

first binding to specific receptors located either on

the plasma membrane or as a cytosolic protein

The receptor for hormones must be linked

to a component that is able to respond to the

binding of hormone that in turn elicits the response

Hormones

Signal Transduction

• Information super highways of the cell.

• Each protein in the pathway typically acts by altering the conformation of the subsequent (downstream) proteins in the series.

• This alteration either activates or inhibits that protein.

• The signal transduction has four properties:

Specificity

Amplification cascade

Desensitization

Integration

Signal Transduction

The series of events and components that

take part in transmitting a hormonal signal to a

the interior of the cell

Membrane or cytosolic Receptor

Signal Initiator

Target molecule

Signal mediator/effector

Action

Signal Transduction

nucleus

cytoplasm

plasma membraneDNA

mRNA protein

steroid hormone blood

proteincarrier

2

3

5

4

S

S

S

1

S

Action of Lipid (steroid) hormones

receptor protein

Action of Protein Hormones

3

4

GTPactivatesenzyme

activatesenzyme

activatesenzyme

Receptorprotein

cAMP

Proteinhormone

ATP

1

2

cytoplasm Produces an action

protein

messenger

cascade

G protein

The 2012 Nobel Prize in Chemistry was awarded jointly to

Robert J. Lefkowitz (l) and Brian K. Kobilka

for

studies of G-protein-coupled receptors

• They are the receptor named just because they interact with G Protein’s.

• Also referred to as “Serpentine Receptor’s” as they contain seven trans-membrane helices (7TM)

• Largest known receptor family – Constitutes > 1% of the human genome.

• Comprises receptors for a diverse array of molecules: neurotransmitters, odorants, lipids, neuropeptides, large glycoprotein hormones

G Protein Coupled Receptor’s (GPCR’s)

G Protein Coupled Receptor’s (GPCR’s)

• Their Structure consists of:

Amino- Terminal: Present on the outside of the cell

Seven α helices: traversing the plasma membrane & connected by loops at varying length

Carboxyl-Terminal: Present on Inside of the cell

• Ligand binding site: three loops that are on outer surface of the cell

• Docking site: three loops that are on inner surface/ cytoplasmic side of the cell; provide site for binding of intracellular protein – G protein’s

G Protein Coupled Receptor’s (GPCR’s)

G Protein Coupled Receptor’s (GPCR’s)

• They are named so because they bind to guanine nucleotide as prosthetic group

GDP – Inactive form

GTP – Active form

• Hetero-trimeric in nature : Three different polypeptide subunits – α, β & γ

• Held at plasma membrane by lipid chains that are covalently attached to the α & γ

G Protein

• The guanine nucleotide binding site is present on Gα subunit:

In GDP bound conformation: Gα subunit has high affinity for the Gβγ; hence they remain together as trimer on cell surface

In GTP bound conformation: Gα subunit has low affinity for the Gβγ; leading to its dissociation from complex

• The two conformations are inter-convertible via activation by GPCR’s; which cause GDP-GTP switching on Gα subunit of trimer.

• Each dissociated Gα subunit in turn is free to activate an effector protein – Like “Adenylyl Cyclase”

G Protein

G Protein

• Thus, Gα subunit is said to be “On” when it is bound to GTP

• Gα subunit turn itself “Off” by hydrolysis of bound GTP via its intrinsic GTPase activity

• The Gα subunit is categorized into four types: Gs: Stimulatory: ↑cAMP levels; ↑Adenylyl cyclase activity; ↑ Cardiac Ca2+

Gi: Inhibitory: ↓cAMP levels ; ↓Adenylyl cyclase activity; ↑ K+ Channels

Gq: Stimulatory: ↑Phopholipase C- B1; ↑IP3; PIK3

G12/13: Unknown: ↑Cl- Channels

• RGS: Regulators of G protein Signaling: Increases the rate of GTP hydrolysis

• GAP: GTPase activating Protein: Increases the rate of GTP hydrolysis

• GEF: Guanosine Exchange factors: cause GTP – GDP switching

G Protein

G Protein

The G Protein Cycle

The G Protein Cascade