Biosignaling and Receptor

Biosignaling

Types of SignalingEndocrine signaling• Signaling molecules act on distant target cells• hormones

Paracrine signaling• Signaling molecules act on nearby target cells• neurotransmitters, growth factors, cytokines

Autocrine signaling• Signaling molecules act on originating cell• tumor growth factors

Juxtacrine signaling• Attached signaling molecules act on adjacent

target cells• integrins, cell adhesion molecules

Signal Transduction PathwaysCommon Elements• Receptor mediated transfer of signal inside

of cell (mostly membrane receptors)– formation of receptor-ligand complex– most ligands remain outside cell

• Relay and amplification of signal from receptor-ligand complex– cascades of protein and enzyme

modifications and product synthesis– GTPase switch proteins, kinases and

phosphatases, second messengers• Termination of signal

– hydrolytic enzymes, membrane transport

Signal

Reception

Transduction

Response(s)

Amplification

Molecular Mechanisms of Signal Transduction

Four general types of signal transducers

Gated Ion ChannelsIon Channels Underlie Electrical Signaling in Excitable Cells

Transmembrane electrical potential

The Nicotinic Acetylcholine Receptor is a Ligand-Gated Ion Channels

CH3-N-CH2CH2O-C-CH3

CH3

CH3 O

+

Voltage-Gated Ion Channels Produce Neuronal Action Potential

Neurons Have Receptor Channels That Respond to A Variety of Neurotransmitters

Glycine, glutamate, serotonin,g-aminobutyric acid (GABA)

Ligand-gated Ion Channels Ligand-gated Ion Channels

• Mis. Reseptor GABA (A-type), Nikotik ACh, 5-HT3 serotonin, glutamat, dan glisin.

• Ligand berinteraksi dg reseptor signal konformasi reseptor kanal ion terbuka ion masuk depolarisasi / hiperpolarisasi Pd R/ GABA-A, interaksi dg R-Benzodiazepin kanal Cl- terbuka

hiperpolarisasi inhibisi fungsi SSP (sedasi)

Pd R/ Nikotinik, interaksi R-ACh kanal Na+ terbuka perubahan membran potensial kanal Ca tebuka aksi potensial depolarisasi ( kontraksi otot bergaris )

• Mis. Reseptor GABA (A-type), Nikotik ACh, 5-HT3 serotonin, glutamat, dan glisin.

• Ligand berinteraksi dg reseptor signal konformasi reseptor kanal ion terbuka ion masuk depolarisasi / hiperpolarisasi Pd R/ GABA-A, interaksi dg R-Benzodiazepin kanal Cl- terbuka

hiperpolarisasi inhibisi fungsi SSP (sedasi)

Pd R/ Nikotinik, interaksi R-ACh kanal Na+ terbuka perubahan membran potensial kanal Ca tebuka aksi potensial depolarisasi ( kontraksi otot bergaris )

GABAA Receptor: chloride channel

Receptor Enzymes

Tyrosine-specific proteinkinase

• Linked directly to tyrosine kinase

Receptor acts as an enzyme receptors

G protein-Coupled Receptors and Second Messengers

Serpentine receptors

b-adrenergic receptor

Gs:Stimulatory G protein(a, b and g subunits)

(Adrenaline)

• G-proteins dalam keadaan inaktif ketika terikat dlm bentuk GDP dan aktif ketika terikat dlm bentuk GTP.

• G-proteins terdiri dari subunit a, b, dan g . Subunit a berinteraksi dg reseptor, dg GDP/GTP, dan dg enzim effector (atau kanal ion).

G-Protein Coupled ReceptorsG-Protein Coupled Receptors

Transmisi Sinyal melewati membran sel terjadi dlm 4 tahap :.

• Ikatan ligand dg reseptor.

• Reseptor mengaktifkan G-protein.

• G-protein yg aktif akan mengaktifkan enzim tertentu atau mempengaruhi kanal ion tertentu.

• Aktivasi enzim menyebabkan perubahan konsentrasi “ second messenger”.

Transmisi Sinyal melewati membran sel terjadi dlm 4 tahap :.

• Ikatan ligand dg reseptor.

• Reseptor mengaktifkan G-protein.

• G-protein yg aktif akan mengaktifkan enzim tertentu atau mempengaruhi kanal ion tertentu.

• Aktivasi enzim menyebabkan perubahan konsentrasi “ second messenger”.

Receptor activationof a G-protein

G-prot regulationof an enzyme orion channel

Change in the cons.of second

messengerInactivation mechanism

Effector

adenylyl cyclase

phospholipase C

Effector

adenylyl cyclase

phospholipase C

2nd messenger

cyclic AMP (cAMP)

calcium, DAG, and

phosphoinositide (IP3)

Adenylat Cyclase (AC) / cAMP System

Receptor

Mechanism of beta-1 receptor activation in cardiac muscle

Ca2+

Effect of beta-2 receptor activation on smooth muscle

Ca2+

G-Protein yg aktif mengaktifkan Phospolipase C (PLC) enzim tsb akan menghidrolisa phosphotidylinositol-4,5-bisphosphate (PIP2) menjadi 2 second messengers : diacylglycerol (DAG) & inositol-1,4,5-triphosphate (IP3).

DAG mengaktifkan protein kinase C (PKC) mempertahankan kontraksi otot polos.

IP3 memobilisasi cadangan calcium dari sarkoplasmik retikulum ke intraseluler Ca intrasel mengawali kontraksi otot polos.

G-Protein juga menyebabkan kanal Ca terbuka Ca intrasel kontraksi otot polos

G-Protein yg aktif mengaktifkan Phospolipase C (PLC) enzim tsb akan menghidrolisa phosphotidylinositol-4,5-bisphosphate (PIP2) menjadi 2 second messengers : diacylglycerol (DAG) & inositol-1,4,5-triphosphate (IP3).

DAG mengaktifkan protein kinase C (PKC) mempertahankan kontraksi otot polos.

IP3 memobilisasi cadangan calcium dari sarkoplasmik retikulum ke intraseluler Ca intrasel mengawali kontraksi otot polos.

G-Protein juga menyebabkan kanal Ca terbuka Ca intrasel kontraksi otot polos

Calcium-Phosphoinositide Second-Messenger System

The Ca2+-Phosphoinositide Signaling Pathway

Rec G PLC PIP2

IP3

Ca2+CaM

E CaM-E*

DAG

PKC

Substrate

ATP ADP

Sub-P

Response

+

cytoplasm

membrane

Mechanism of alpha-1 receptor activation of smooth muscle contraction

Activation of cAMP-dependent protein kinase, PKA

a C subunit of PKA

PKI

ATP

Guanylyl Cyclase is a Receptor Enzyme that Generates The Second Messenger cGMP

Atrial Natriuretic Factor Heart ANF Kidney ANF/ANFR cGMP

Na+/H2O out

(diarrhea)

cGMP-dependent protein kinase PKG

Epinephrine Cascade

Degradation of cAMP by Cyclic Nucleotide Phosphodiesterase

Calcium Is a Second Messenger in Many Signal TransductionsCalmodulin (CaM)

CaM kinase II peptide

Intracellular Actions: Regulation of Gene Transcription

Intracellular Actions: Regulation of Gene Transcription

Cytosolic receptors. Steroid hormon menembus membran sel dan mengikat reseptor di sitoplasma. Kompleks ligand-reseptor ditranspor masuk ke nukleus dan berikatan dg rantai DNA untuk meregulasi transkripsi gen.

Nuclear receptors. Thyroid hormon masuk ke dalam sel dan secara pasif masuk ke nukleus untuk berikatan dengan reseptornya.

Cytosolic receptors. Steroid hormon menembus membran sel dan mengikat reseptor di sitoplasma. Kompleks ligand-reseptor ditranspor masuk ke nukleus dan berikatan dg rantai DNA untuk meregulasi transkripsi gen.

Nuclear receptors. Thyroid hormon masuk ke dalam sel dan secara pasif masuk ke nukleus untuk berikatan dengan reseptornya.

Intracellular Mechanism: Steroid

Plasma

R

Nucleus

R

XXXXXXXXXXXXX

RNA

mRNAProtein

Effects

receptors

• Nuclear receptors that

regulate gene

transcription

Regulation of Transcription by Steroid Hormons