Signal transduction The process of converting extracellular signals into cellular responses. extracellular signaling molecules (ligands) synthesized and released by signaling cells produce a specific response only in target cells that have receptors for the signaling molecules Receptor protein that specifically binds a signaling molecule to initiate a response in a target cell Cell responses : changes in gene expression, morphology, movements…

Signal transduction

kinase cascade a series of protein kinases that phosphorylate each other in succession amplifies the signal because a few signal molecules can elicit a large cell response

Hormones are often present at mico or nanogram/liter quantities in the blood. Amplification creates massive effects in the target cell

Signal transduction Communication by extracellular signals usually involves six steps: (1) synthesis and (2) release of the signaling molecule by the signaling cell (3) transport of the signal to the target cell (4) detection of the signal by a specific receptor protein (5) change in cellular metabolism, function, or development triggered by the receptor-signal complex (6) removal of the signal, which often terminates the cellular response

Classification of hormones based on solubility and receptor location Small lipophilic molecules diffuse across the plasma membrane and interact with intracellular receptors steroids, thyroxine and retinoic acid Water-soluble hormones with cell-surface receptors Peptide hormones (insulin, growth factors, glucagon) Small charged molecules epinephrine, histamine Lipophilic hormones with cell surface receptors Prostaglandins (prostacyclins, thromboxanes, leukotrienes )

Two general types of receptors Cell surface receptors LIGAND – hydrophilic signaling molecules Intracellular receptors LIGAND – hydrophobic signaling molecules

Major classes of cell surface receptors G-protein coupled receptors epinephrine, serotonin, glucagon receptors Ion channel receptors Acetylcholine receptor Tyrosine kinase-linked receptors receptors for cytokines, growth factors Receptors with intrinsic enzymatic activity receptors for insulin and growth factors

TYPES OF SECOND MESSENGERS GASES NO H2S  CO HYDROPHOBIC Diacylglycerol Phosphatidylinositols HYDROPHILIC cAMP cGMP IP3 Ca2+. 3’,5’ cyclic AMP (cAMP) 3’,5’ cyclic GMP (cGMP) 1,2 diacylglycerol (DAG) inositol 1,4,5 triphosphate (IP3) inositol phospholipids (phosphoinositides) Ca++

Signaling via G-protein-coupled receptors (GPCR) G-Proteins – GTP-binding proteins Trimeric proteins ( α β γ ) Coupled directly to activated receptors GTPases – convert GTP to GDP + Pi ACTIVE- when GTP is bound INACTIVE – when GDP is bound

G-protein coupled receptor

G-protein coupled receptor

Cyclic AMP (cAMP) Second messenger produced from hydrolysis of pyrophosphate from ATP Synthesized by Adenylyl Cyclase Degraded by cAMP phosphodiesterase to form 5’AMP.

Cyclic-AMP-dependent Protein Kinase (PKA) Mediates Most of the Effects of Cyclic AMP

cAMP activate glycolysis

How gene transcription is activated by a rise in cyclic AMP concentration

G Proteins Activate Inositol Phospholipid Signaling Pathway Many G-Protein-Linked receptors exert their effects mainly via G proteins that activate the plasma-membrane-bound enzyme phospholipase C Phosphatidyl inositol 4,5-bisphosphate  diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) the signaling pathway splits into two branches. IP3 releases Ca++ from ER DAG together with bound Ca++ activates protein kinase C C-Kinase phosphorylates cell proteins

Diacylglycerol Diacylglycerol stimulates protein kinase C activity by greatly increasing the affinity of the enzyme for calcium ions. Protein kinase C phosphorylates specific serine and threonine residues in target proteins. Known target proteins include calmodulin, the glucose transporter, HMG-CoA reductase, cytochrome P450 etc.

Receptor Kinases Receptor tyrosine kinases -membrane receptor -when bound by a ligand, the receptor is activated by dimerization and autophosphorylation -activated receptor adds a phosphate to tyrosine on a response protein -an example is the insulin receptor

Families of receptor tyrosine kinases

mitogen-activated protein kinases

Other second messengers cGMP is synthesized from GTP using the enzyme guanylyl cyclase Some of the effects of cGMP are mediated through Protein Kinase G (PKG) nitric oxide (NO) stimulates the synthesis of cGMP cGMP serves as the second messenger for NO Ca++: altering intracellular [Ca++ ] Ca++ binds to, and activates an enzyme binds to an intermediary cytosolic calcium binding protein such as calmodulin, then calmodulin bind to effector

Ras/Raf/MAP Pathway: The Ras/Raf/MAP pathway mediates the effect of many growth factors and mitogens. Ras, which is a proto-oncogene product, functions like a G-Protein and conveys the signal (by GDP/GTP exchange) from the SH2-domain protein Grb, which is phosphorylated by the receptor tyrosine kinase. Activation of Ras, in turn, activates Raf, which is the first of a sequence of serine/threonine kinases, each of which phosphorylates, and activates, the next in line. The last of these, MAP (Mitogen-Activated Protein) kinase, phosphorylates one or more transcription factors that initiate gene expression, resulting in a variety of cellular responses, including cell division.

Jak/Stat pathway The Jak/Stat pathway is involved in responses to many cytokines. Dimerisation of these receptors occurs when the cytokine binds, and this attracts a cytosolic tyrosine kinase unit (Jak) to associate with, and phosphorylate, the receptor dimer. Among the targets for phosphorylation by Jak are a family of transcription factors (Stats). These are SH2-domain proteins that bind to the phosphotyrosine groups on the receptor-Jak complex, & are themselves phosphorylated. Thus activated, Stat migrates to the nucleus and activates gene expression.

Intracellular receptors

Ex Biochem c5-oxid phosphoryl