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

Up regulation Down regulation

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++

Ion Channels• Messenger binds to a plasma

membrane receptor which opens or closes an ion channel

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++

cAMPAdenylyl cyclase

Adenosine triphosphate (ATP) Cyclic adenosine monophosphate (cAMP)

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

Cell signaling

Two pathways that can lead to cancer