chapter 14 signal transduction mechanisms: ii. messengers and receptors

Chapter 14

Signal Transduction Mechanisms: II. Messengers and

Receptors

• Cell-to-cell Communication is absolutely essential and important for multicellular organisms.– Cells must communicate to coordinate their

activities.• Biologists have discovered some universal

mechanisms of cellular regulation, involving the same small set of cell-signaling mechanisms.

• Cells may receive a variety of signals, such as chemical signals, electromagnetic signals, and mechanical signals.

• The process by which a signal on a cell’s surface is converted into a specific cellular response is a several steps in a signal-transduction pathway.

Signal Transduction Mechanisms II. Messengers and Receptors

• Chemical Signals and Cellular Receptors

• G Protein-Linked Receptors

• Protein Kinase-Associated Receptors

• Growth Factors as Messengers

• The Endocrine and Paracrine Hormone Systems

• Cell Signals and Apoptosis

Chemical Signals and Cellular Receptors

• Different types of chemical signals can be received by cells

• Receptor binding involves specific interactions between ligands and their receptors

• Receptor binding activates a sequence of signal transduction events within the cell

• All cells have some ability to sense and respond to specific aspects of their environment

– Physical factors: light (retina), sound (hair cells), heat, or gravity

– Chemical factors: extracellular molecular- receptor on tongue

– One cell can release chemical signals that are recognized by another cells, either nearby or at a distant location

Different Types of Chemical Signals Can Be Received by Cells

• Chemical signals– Hormones: produced at great distances from their target

tissues and carried in the circulatory system to various sites– Growth factors: released locally, acting on nearby tissue

• Many messengers are Hydrophilic Compounds:– First messenger: Ligand– Second Messenger: such as cyclic AMP and calcium– Signal transduction: the ability of a cell to translate a

Receptor-Ligand Interaction to change in its behavior or gene expression

• Hydrophobic messengers– Act on nuclear receptors or cytosol, regulate the transcription

of particular genes– Steroid hormones

Receptor Binding Involves Specific Interactions Between Ligands and Their Receptors

• How do cells distinguish messengers from the environment–Highly specific way: the messenger molecule binds to the receptor–A messenger forms noncovalent chemical bonds with the receptor

protein alteration

• Receptor Affinity- Kd: dissociation constant• Receptor Down-Regulation: desensitization is due mainly

to changes in the properties or cellular location of the receptor Removal of the receptor from the cell surface: receptor-mediated

endocytosis Alteration to the receptor that lower its affinity for ligand Alteration to the receptor that render it unable to initiate change

in cellular function

• Nasal spray: receptor down-regulation

Two Classes of G Protein• Large heterotrimeric G proteins

– G: largest one bind to GTP or GDP– G and G always bind together– GTP-G , GTP-G regulate different processes– Gs or Gi

• Small monomeric G proteins– Ras related to

• Tyrosine kinase receptor• Cytoskeleton

• Activate ion channel or enzyme activity

• Different effects of cAMP concentration

– Breakdown of glycogen in muscle or liver cells

– Increase heart contraction

– Inhibit the movement of blood platelets

– Increase the secretion of salts and water in intestinal epithelial cells

Disruption of G Protein Signaling Causes Several Human Diseases

• Salts and fluid in the intestine are regulated by hormones that act through the G protein Gs to alter intracellular levels of cAMP

• Certain microbes cause disease by disrupting the G-protein signaling pathways– The cholera bacterium, Vibrio cholerae ( 霍亂弧菌 ),

colonizes the the small intestine and produces a toxin that modifies a G protein that regulates salt and water secretion.

– The modified G protein is stuck in its active form, continuously stimulating productions of cAMP.

– This causes the intestinal cells to secrete large amounts of water and salts into the intestines, leading to profuse diarrhea and death if untreated.

• Because cytosolic Ca2+ is so low, small changes in the absolute numbers of ions causes a relatively large percentage change in Ca2+ concentration.

• Many signal molecules in animals induce responses in their target cells via signal-transduction pathways that increase the cytosolic concentration of Ca2+.– Signal-transduction pathways trigger the release of Ca2+ from

the cell’s ER.

• The pathways leading to release involve still other second messengers, diacylglycerol (DAG) and inositol trisphosphate (IP3).– Both molecules are produced by cleavage of certain

phospholipids in the plasma membrane.

• Cells use Ca2+ as a second messenger in both G-protein pathways and tyrosine-kinase pathways.

The Release of Calcium Ions is a Key Event in Many Signaling Processes

Calcium Oscillation

• Neurons• Fertilized Mammalian Eggs• Opening and Closing of Stomata (氣孔 ) in Plants

• Most signal molecules are water-soluble and too large to pass through the plasma membrane.

• They influence cell activities by binding to receptor proteins on the plasma membrane.– Binding leads to change in the shape of the receptor

or to aggregation of receptors.– These trigger changes in the intracellular

environment.

• Three major types of receptors are G-protein-linked receptors, tyrosine-kinase receptors, and ion-channel receptors.

Most Signal Receptors are Plasma Membrane Proteins

• The tyrosine-kinase receptor system is especially effective when the cell needs to regulate and coordinate a variety of activities and trigger several signal pathways at once.

• Extracellular growth factors often bind to tyrosine-kinase receptors.

• The cytoplasmic side of these receptors function as a tyrosine kinase, transferring a phosphate group from ATP to tyrosine on a substrate protein.

Receptor Tyrosine Kinase Aggregate and Undergo Autophosphorylation

Protein Kinase-Associated Receptors• Receptor tyrosine kinases aggregate and undergo autophosphorylation

– Add phosphate groups to particular amino acids– Trigger a chain of signal transduction event- lead to cell growth,

proliferation or differentiation.• Receptor tyrosine kinases initiated a signal transduction cascade

involving Ras and MAP kinase:– GNRP (guanine-nucleotide release protein) = Sos + GRB2

• SH2 domain– Ras: small monomeric G protein – the growth of cells.– MAPK (MAP kinase): mitogen-activated protein kinases– AP-1: Transcription Factor

• Receptor tyrosine kinases activate a variety of other signaling pathway – PLC: phospholipase C ( 磷脂酶 C)

• PLC-: activated by receptor tyrosine kinase• PLC-: activated by G protein-linked receptors

• Ligand-gated ion channels are very important in the nervous system.– Similar gated ion channels respond to electrical

signals.

• A cell targeted by a particular chemical signal has a receptor protein that recognizes the signal molecule.– Recognition occurs when the signal binds to a specific

site on the receptor because it is complementary in shape.

• When ligands (small molecules that bind specifically to a larger molecule) attach to the receptor protein, the receptor typically undergoes a change in shape.– This may activate the receptor so that it can interact

with other molecules.– For other receptors this leads to aggregation of

receptors.

A Signal Molecule Binds to a Receptor Protein Causing the Protein to Change Shape

In contrast to growth factors, hormone often act over large distance via circulatory system

• Hormone differ in many ways– Steroids or other hydrophobic molecule:

intracelllular receptor – Adrenergic hormones ( 腎上腺荷爾蒙 ):

G-protein link receptor – Insulin: ligands for receptor tyrosine

kinase• Act on the target cells: adrenal gland ( 腎上

腺 ) – epinephrine ( 腎上腺素 )

Exocrine 外分泌

• Digestive tissue/system ( 消化系統 )

Apoptosis( 細胞凋亡 ) 作用真核細胞的死亡可由形態學及生化特性區分為細胞

壞死 (necrosis) 及細胞凋亡 (apoptosis) 。與細胞壞死的被動過程不同，細胞凋亡並不是病體條件下自體損傷的一種現象，而是為維持內部穩定適應生存環境而主動採取的一種死亡過程。就像樹葉或花的自然凋落一樣，借用希臘詞 “ apoptosis” 來表示，可譯為“細胞凋亡”。

細胞凋亡作用發生時，細胞膜發生皺縮、胞質濃縮、染色質變得緻密，內源性核酸內切脢激活後，將染色體剪切成單個或是寡核小體，這些核小體由 histone 與 180 bp

長的 DNA 片段緊密結合所組成，在電泳圖上可看出階梯狀的 DNA-ladder 。

Apoptosis Is Triggered by Death Signals or Withdrawal of Survival Factors

• Two well-known death signals are received by

– Tumor necrosis factor receptor

– CD95/Fas receptor

• Cells require tropic, or survival factors to stay alive

– Cytokines in bloodstream as survival factors

Cell signals and Programmed cell death

• Cells were infected by certain viruses, then killer lymphocytes are activated and induce the infected cells to initiate apoptosis– Fas ligand (CD95 ligand) on the surface of killer

lymphocyte – CD95/Fas receptor on the surface of the target cells

chapter 14 signal transduction mechanisms: ii. messengers and receptors

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