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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