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Chemical messengers and cell signaling
Chemical messengers and Chemical messengers and cell signaling cell signaling
Dr. Carmen E. Dr. Carmen E. RexachRexachMtSACMtSAC Biology DepartmentBiology Department
PhysiologyPhysiology
Cellular communication• All cells receive and respond to signals• Signaling molecules are produced by
cells and bind to receptors on cell surfaces– Regulate all aspects of cellular behavior– Initiate intracellular reactions in response
to binding– Breakdown in the signaling pathways
governing cell proliferation and cellular survival can lead to disease states, such as cancer
Receptors• Follow the same binding
rules– Chemical specificity– Competition– Saturation– Affinity
• A single type of receptor for a particular messenger may elicit a totally different response in different cell types
Signaling molecules• Molecules that bind to receptors are
called ligands• Many different types are produced
– Range from simple gases to proteins– Include neurotransmitters and
hormones• Some effect cells in immediate
neighborhood, some over long distances
• Some bind to receptors on the cell surface, some inside the cell
Spectrum of cell-cell signaling• Endocrine
– molecular signal from endocrine cell through the blood stream to distant target cell
• Neurocrine– molecular signal from axon of
nerve cell into blood stream to relatively distant target cell
• Paracrine– molecular signal from one cell
type to neighboring different cell type by diffusion
• Autocrine– molecular signal from one cell
back to cell of origin
Regulation of receptors• Downregulation
– Chronically high levels of chemical messenger in ECF
– Decrease in number of receptors for that messenger
– “Desensitizes” cell to the messenger• Upregulation
– Chronically low levels of chemical messenger in ECF
– Increase in the number of receptors– Makes the cell more sensitive to the messenger
Response to receptor activation
• Change in permeability, transport properties, electrical state of plasma membrane
• Change in cellular metabolism• Change in secretory activity• Change in rate of proliferation and
differentiation• Change in contractile activity
Location of receptor
• Receptors for molecules that are hydrophilic are located on the surface of the cell = plasma membrane receptors
• Receptors for molecules that are hydrophobic are located inside the cell, either in cytoplasm or in the nucleus = intracellular receptors
Receptor function by location
• Intracellular receptors– Function as transcription factors or
suppressors– Alter the rate of gene transcription
• Plasma membrane receptors– Function as ion channels– Function as enzymes– Activate G-proteins – Bind to and activate cytoplasmic JAK kinases
Cell surface receptors and signal transduction pathways
• Binding of regulatory substances (such as neurotransmitters or hormones) to receptors in the plasma membrane results in a response inside of the cell by downstream signaling
ECF
Plasma membrane
cytosol
Pathway components• 1)First messenger
– Chemical messenger that arrives at cell from ECF and activate receptor
• 2)Second messenger– Come into cell or are produced in the cell due
to receptor activation• 3) protein kinase
– Phosphorlyates other proteins
Signal transduction pathwaysSignal 1 Signal 2 Signal 3
receptor receptor receptor
ECF
Plasmamembrane
cytosolcAMP Ca++ PL-C
PK-A Calmodulin DAG + IP3
Protein kinase PK-C Ca++
G protein-coupled receptors• Structurally composed of 7 helices that
span the membrane of the cell– Binding of ligands causes them to change shape– Allows portion of receptor in cytosol to bind to
and activate a G protein– Activated G protein dissociates and carries a
signal to some other target inside cell (signal transduction pathway)
N
C
ECF
Plasma membrane
cytosol
G protein-coupled receptors
αβγ
Adenylyl cyclase
ATP cAMP
G protein ActivatedG protein
α α
ECF
Plasma membrane
cytosol
receptor
Protein-tyrosine kinase receptors• Directly linked to intracellular
enzymes• Often involved in control of cell
growth and differentiation• Structural organization
– N-terminal extracellular ligand-binding domain
– Single transmembrane alpha helix
– C-terminal domain with protein-tyrosine kinase activity
– Sometimes single receptors, sometimes dimerize
N N
C C
TyrosineKinasedomain
ECF
Plasma membrane
cytosol
PTK receptors• When activated:
– Ligand binds to extracellular domains– Kinase domain in cytosol is activated– Results in phosphorylation of receptors
and target proteins in the cell– Signal is propagated within the cell by
downstream signaling molecules
Protein-tyrosine kinase receptors
ECF
Plasma membrane
cytosol
N
C
N
C
ligand
P
PP
P
P
P
N
C
N
C
ligand
Downstream signaling molecules
Signal transduction pathways and second messengers
• Definition– Chain of reactions that take signal from
surface to targets inside the cell• Function
– Propagate and amplify signal– Connect the cell surface with the nucleus
• Lead to changes in gene expression in response to outside signals
• Second messenger systems– cAMP– Phospholipids and Ca++
cAMP as a second messenger
• Enzyme, adenylyl cyclase, converts ATP to cAMP
• G protein connects extracellular receptor to enzyme and amplifies concentration of cAMP in cell
• cAMP binds to and activates protein kinase A
• Leads to phosphorylation of target proteins
G protein-coupled receptorsand cAMP
receptor
αβγ
Adenylyl cyclase
ATP cAMP
G protein ActivatedG protein
α α
ECF
Plasma membrane
cytosol
Protein kinase A Protein kinase A
P
Phospholipids and Ca++
• Activated downstream by both G proteins and protein tyrosine-kinases
• PIP2 (phosphatidylinositol 4,5-biphosphate) is found on the inside phospholipid bilayer in plasma membrane
• Converted by enzyme, PLC (phospholipase C) to two second messengers– DAG (diacylgycerol)– IP3 (inositol 1,4,5-triphosphate)
• Each stimulates a different signal transduction pathway– DAG = activation of protein kinase C– IP3 = Ca++ mobilization
Protein-tyrosine kinasereceptors
N
C
N
C
ligand
P
PP
P
P
P
N
C
N
C
ligand
PIP2
PLC
DAG
IP3
IP3
Ca++
calmodulinCa++
Ca++
PK
PK
PKCPKC
Ca++ as a second messenger
• Increased cytosolic Ca++
– Receptor activation• First messenger activates channel• G protein uses second messenger to activate channel• Remember: Ca++ higher outside!
– Opening of voltage gated Ca++ channels• Change in membrane potential causes a conformational
change that opens the channel
Ca++ as a second messenger• Cellular response to increased Ca++
– Ca++ binds to calmodulin• Calmodulin changes shape and turns off or on
enzymes and other proteins• Ex) calmodulin dependent protein kinases
– Ca++ binds to other calcium binding intermediary proteins
– Ca++ binds to and alters other proteins directly• Ca++ binds to troponin, allowing muscle cells to
contract
Eicosanoids• Produced in plasma membrane by cells in response to
stimuli• Act like intracellular second messengers of hormones• Precursor
– arachadonic acid (formed from essential fatty acid = linolenic acid)
– Tissue specific enzymes can convert this to:• Leukotrienes• Cyclical endoperoxides
– Prostaglandins– Thromboxanes
NOTE: The production of eicosanoids is effected by eating certain foods, such as Vitamin C, garlic, onion, ginger, and alcohol!
receptor
First messenger
Phospholipase A2
Arachadonic acid
Cyclical endoperoxides
Leukotrienes
Prostaglandins Thromboxanes
lipooxygenasecyclooxygenase
Prostaglandins• Major role: control vascular smooth muscle activity
– Localized action on microcirculation adjust flow of blood due to metabolic changes
– some vasoconstrict, some vasodilate• Example: cause vasodilation in renal medulla leading
to increased blood flow and increased secretion of electrolytes
• Also involved in– immune response– uterine contraction – Inhibition of gastric secretions
• can be relieved by NSAID’s– Inhibits the step mediated by cyclooxygenase
Leukotrienes• Made by leukocytes• Major role: vascular contraction and
vascular permeability• Induce inflammatory response
– White blood cells act like wandering endocrine glands producing leukotrienesat sites of infection
– Also involved in allergic reactionsNote: Glucocorticoids (adrenal steroids) restrict the production of all eicosinoids…that may be why an increase in glucocorticoids is immunosuppressive!
Turning off the pathway• 1)decrease in concentration of first
messenger in ECF• 2)inhibitory phosphorylation of
receptor decreases affinity for messenger
• 3)endocytosis of first messenger and receptor
Other functions of intracellular signaling
• Signal transduction mechanisms are involved in many other functions in the cells beside metabolism
• Examples– Receptors on the cell surface called integrins
signal changes in the cytoskeleton of the cell that allow for many important processes, such as:
• Adhesion• Diapedesis• Cell motility• Wound healing • Embryonic development• Cytokinesis• Regulation of muscle contraction
Cancer and signal transduction• All cancers are characterized by the
abnormal proliferation of cancer cells• Mutations in the genes of normal
cells can convert them to oncogenesand result in cancer
• Many of these oncogenes cause signal transduction pathways that lead to cell proliferation to be continually turned on in the absence of signaling molecules
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