Biosignaling and Receptor

Biosignaling

Types of Signaling
Endocrine signaling
Signaling molecules act on distant target cells hormones Signaling molecules act on nearby target cells neurotransmitters, growth factors, cytokines Signaling molecules act on originating cell tumor growth factors

Paracrine signaling

Autocrine signaling

Juxtacrine signaling

Attached signaling molecules act on adjacent target cells integrins, cell adhesion molecules

Signal Transduction Pathways

Signal

Common Elements Receptor mediated transfer of signal inside of cell (mostly membrane receptors)
formation of receptor-ligand complex most ligands remain outside cell

Reception

Amplification
Transduction

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
Response(s) hydrolytic enzymes, membrane transport

Molecular Mechanisms of Signal Transduction

Four general types of signal transducers

Gated Ion Channels

Ion Channels Underlie Electrical Signaling in Excitable Cells

Transmembrane electrical potential

The Nicotinic Acetylcholine Receptor is a Ligand-Gated Ion Channels

CH3 CH3-N-CH2CH2O-C-CH3 CH3
+

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

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

Tyrosinespecific protein kinase

 Linked directly to tyrosine kinase

Receptor acts as an enzyme

receptors

G protein-Coupled Receptors and Second Messengers

(Adrenaline)

Serpentine receptors b-adrenergic receptor Gs: Stimulatory G protein (a, b and g subunits)

G-Protein Coupled Receptors 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).

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 activation of a G-protein

Change in the cons.of second messenger

Inactivation mechanism

G-prot regulation of an enzyme or ion channel

Effector

2nd messenger

adenylyl cyclase
phospholipase C

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+

Calcium-Phosphoinositide Second-Messenger System

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

The Ca2+-Phosphoinositide Signaling Pathway

Rec

PLC

PIP2

DAG +

membrane

cytoplasm Ca2+
E

IP3

PKC
ATP ADP

CaM CaM-E*

Substrate

Sub-P

Response

Mechanism of alpha-1 receptor activation of smooth muscle contraction

Activation of cAMP-dependent protein kinase, PKA

ATP

PKI a C subunit of PKA

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

(diarrhea)

cGMP-dependent protein kinase PKG

Atrial Natriuretic Factor Heart ANF Kidney ANF/ANFR cGMP Na+/H2O out

Epinephrine Cascade

Degradation of cAMP by Cyclic Nucleotide Phosphodiesterase

Calcium Is a Second Messenger in Many Signal Transductions Calmodulin (CaM)

CaM kinase II peptide

Intracellular Actions: Regulation of Gene Transcription

Cytosolic receptors. Steroid hormon menembus membran sel

dan mengikat reseptor di sitoplasma. Kompleks ligandreseptor 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

Nucleus
XXXXXXXXXXXXX

Effects

RNA

Protein

mRNA

Plasma

 Nuclear receptors that regulate gene transcription

receptors

Regulation of Transcription by Steroid Hormons