Cell Communication: Hormones, Growth factors and Neurotransmitters

• cells can communicate with those right next to them or can communicate with targets at a distance

• communication can be through direct contact = adhesion-based mechanisms OR transfer of materials through gap junctions

• or through the production of extracellular factors called signals – -e.g. hormones, neurotransmitters, neuropeptides, growth factors

• this is called extracellular signaling

• these compounds exert their effects by binding to the target cells and/or entering the cell

• the ultimate goal is to affect the function of the cell– through modifying the expression of genes/proteins

Cell Communication: Hormones, Growth factors and Neurotransmitters

-6 steps to extracellular signaling:1. synthesis of signal (hormone, NT)2. release of signal (exocytosis)3. transport of signal to target (local? distance?)4. detection of signal by target (binding to receptors)5. change in target cell function6. removal of the signal & loss of effect

-three types of extracellularchemical messengers:1. paracrines (e.g. growth factors)2. neurotransmitters3. hormones

Extracellular Signaling: Mechanisms

growth factors

hormones, NTs, growth factors

hormones

• most signals produced by cells within the body bind to receptors that are specific for that signal

• most receptors are found on the cell surface• although some can be found within the cell• binding of the signal (ligand) to the receptor results in a series of

events (signal transduction) within the cell that changes the cells function– e.g. may change the transcription rate of a gene – effects protein

production

Extracellular Signaling: Mechanisms

1. Ion channel – ion channel (transmembrane protein) acts as a receptor for a signal (ligand)- binding of the ligand to the ion channel changes the conformation of the receptor and allows transit of a specific ion through it-this allows entry of the signaling ion-responsible for the changing of membrane potentials-once the signal is removed the channel closes

-many ion channels open and close through a portion of theprotein that acts like a “gate”

NTs

Extracellular Extracellular Signaling: Signaling:

MechanismsMechanisms

2. G-protein Coupled Receptor (GPCR) – binding of the signal (S) to its Receptor activates the R-the R binds to and activates an adjacent plasma membrane protein = called a G protein-the G protein effects the activity of another plasma membrane protein called an Effector (E)

e.g. most common - adenylyl cyclase or adenylate cyclase (AC)-Effector then creates a second message within the cell

e.g. AC converts ATP to cAMP (cyclic AMP)-cAMP acts as a signal within the cell = second messenger – effects cell activity

-BUT some G proteins can inhibit this pathway!!!! (no AC activation, no cAMP production)

HORMONESNeurotransmitters

5 players in this mechanism:1. Hormone (1st messanger)2. Receptor = GPCR3. G protein (stimulatory or inhibitory)4. Effector – adenylate cyclase, PLC 5. Second messanger = cAMP, calcium

3. Receptor Tyrosine-linked kinases (RTKs)– binding of the signal to the Receptor causes the R to dimerize (pair-up)-the R activates enzymes called kinases-an activated kinase then goes on to activate another target by phosphorylating it (adding a phosphate group)

KINASE = protein that phosphorylates a Target protein

-binds and breaks down ATP into ADP + Pi-kinase takes this Pi and attaches it to itstarget-this activates the target-most of the time the target is another

kinase-this second kinase phosphorylates its target

= kinase cascade results

GrowthFactors

KINASE CASCADE

d) Receptor Tyrosine-linked Kinases = Growth factors

GF binding Receptor dimerization& activation

Activation of kinases

Hormones: Mechanisms of Signaling

• hormone producing cell = endocrine cell

• can use three mechanisms• Autocrine signaling

– cell responds to the hormone it produces

• Paracrine signaling– local action– local hormone (paracrine

hormones) act on neighboring cells– autocrines act on same cell that

secreted them• Endocrine signaling

– circulating hormones (endocrine hormones)

– act on distant targets– travel in blood

Types of Hormones

• water-soluble• lipid -soluble

Lipid-soluble Hormones• Steroids

– lipids derived from cholesterol – made in SER– different functional groups attached to

core of structure provide uniqueness• e.g. cortisol, progesterone, estrogen,

testosterone, aldosterone

• Thyroid hormones– tyrosine ring plus attached iodines

• Retinoic acid– lipids derived from retinol (vitamin A)– regulate proliferation, differentiation

and death of many cell types• some vitamins can acts a lipid-soluble

hormones– e.g. vitamin D

• Nitric oxide (NO)- gas

testosterone aldosterone

cortisol

• Eicosanoids– prostaglandins or leukotrienes– derived from the fatty acid called

arachidonic acid – arachidonic acid is used as a

starting point for making either prostaglandins or leukotrienes

– both act in the inflammatory reaction

• e.g. stimulate smooth muscle cells to contract

• e.g. stimulate nerve cells – pain– conversion of arachidonic acid into

prostaglandins is regulated by the COX enzymes

• these enzymes are targeted by anti-inflammatories like aspirin, ibuprofen, Vioxx

Lipid-soluble Hormones

• synthesis of steroid hormones from cholesterol backbone requires a series of specific enzymatic reactions that modifies the cholesterol– these enzymes are specific for each steroid made– they are located in specific cell types

• not stored – once formed they released by diffusion through into the blood– require binding to a carrier protein to be transported in the blood– carrier proteins can be specific or some can pick up any steroid hormone

• only cholesterol is stored in the cytoplasm

Lipid-soluble Hormones

Water-soluble Hormones• Amine, peptide and protein hormones

– range from modified amino acids to protein chains

– serotonin, melatonin, histamine, epinephrine, insulin, dopamine

– protein hormones – comprised of one or many polypeptide chains

• insulin, glucagon– peptide hormones – comprised of chains of

amino acids• e.g. growth hormone, oxytocin

– amine hormones – derived from the amino acids tyrosine or tryptophan

• epinephrine and norepinephrine(tyrosine), serotonin (tryptophan), dopamine (tyrosine)

• one subcategory is called the catecholamines: epinephrine, norepi. and dopamine

• can also act as neurotransmitters

insulin

• water-soluble hormones are synthesized and secreted using the same mechanism that regulates the secretion of any other protein– made as precursors in the ER – called preprohormones– transport to the Golgi where they are “pruned” to give rise to

the active hormone– packaged and secreted from the Golgi– stored in the cytoplasm until needed– secretion is triggered only by specific stimulus

Water-soluble Hormones

Action of Lipid-Soluble Hormones: Endogenous signaling

• Lipid-soluble hormone must be carried by a carrier/transport protein that allows it to dissolve within the aqueous environment of the blood plasma

• Hormone diffuses through phospholipid bilayer & into target cell

• the Receptor is located within the cell (cytoplasm or the nucleus)

• binding of H to R in the cytoplasm results in its translocation into the nucleus

• the H then binds directly to specific sequences within the DNA = response elements

• this binding turns on specific genes – activates or inhibits gene transcription

• new mRNA is formed & directs synthesis of new proteins

– new protein alters cell’s activity

Action of Lipid-Soluble Hormones– For an animation:

http://highered.mcgraw-hill.com/sites/0072943696/student_view0/chapter10/animation__mechanism_of_steroid_hormone_action__quiz_1_.html

Action of Lipid-Soluble Hormones

• some lipid-soluble hormone don’t cross the plasma membrane – too large

• therefore they bind with receptors on the cell surface and trigger signaling events within the cells– signal similar to water-soluble hormones– e.g. prostaglandins and leukotrienes

• easily travels through the blood - hydrophilic

• but cannot diffuse through plasma membrane!

• therefore they require the expression of Receptors on the cell surface – integral membrane proteins

• the Receptor protein activates a series of signaling events within the cells– e.g. epinephrine binds to receptor and

activates an adjacent G-protein in membrane

– G-protein activates adenylate cyclase to convert ATP to cyclic AMP (cAMP) in the cytosol

– cAMP acts as a 2nd messenger– protein cascade results

Action of Water-Soluble Hormones

– cAMP activates its target = kinase

– kinases act to phosphorylate their targets

– kinase cascade results– physiological response occurs

within the cell– phosphodiesterase

inactivates cAMP quickly• Cell response is turned off unless

new hormone molecules arrive• this mechanism allows for

amplification – one H-R combination can activate two G proteins which activates 4 kinases which activate 16 more kinases etc…….

Kinase cascades amplify hormone signals

Action of Water-Soluble Hormones

-animations: go to you tube and search“G protein animation” OR-http://highered.mcgraw-hill.com/sites/0072943696/student_view0/chapter10/animation__second_messenger__camp.html

• so the binding of a hormone to a receptor results in downstream cellular events

• either through direct activity of the receptor (activated by the ligand) or through production of a second messenger– types of second messengers:

• 1. cAMP: produced by adenylate cyclase/AC (activated by hormone G protein interaction)

• 2. calcium– -IP3 & DAG

Action of Water-Soluble Hormones

• cell expresses numerous type of G proteins that interact with the GPCRs– some activate adenylate cyclase and stimulate

production of cAMP – Gs (G stimulatory)– others inhibit AC – Gi (G inhibitory)

Gs protein

Adenylate cyclase

G proteinsG proteins

• best studied system: binding of epinephrine to the 2-adrenergic receptor• activates a Gs protein and produces cAMP

– Gs protein is comprised of three subunits – alpha, beta, gamma– the active subunit is the alpha subunit– however the beta and gamma subunits have signaling roles also– note the Gs subunit cycles between GTP and GDP bound states – called a GTPase protein– the cycling between GTP and GDP helps control its function– ANIMATION: http://www.youtube.com/watch?v=NMeBZlbs2dU

cAMP Second Messenger systems

• the ability to bind and hydrolyze GTP determines the function of the Gs subunit

• also the site at which bacterial toxins can affect this signaling path• the hydrolysis of the GTP on the Gs protein is catalysed by the Gs protein

itself

cAMP Second Messenger systems

• cholera “locks” the Gs alpha subunit into its GTP-bound “ON” state

• persistent activation of adenylate cyclase

• severe disruption of water absorption by GI tract

• can be fatal within hours

• the activity of AC can be modified also by interactions with a Gi protein

• therefore the cell can modify its level of cAMP made by stimulating the GPCRs that activate either Gs or Gi proteins

• the alpha subunit of the Gi protein (Gi) also interacts with AC (at a different location)– prevents its activity – no second messenger made

• this Gi protein is also an GTPase and requires the binding of GTP to become active and inhibit AC – once GTP is hydrolyzed the protein dissociates the AC inhibition is relieved

cAMP Second Messenger systems

• cAMP phosphorylates a class of kinases called cAMP-dependent protein kinases (PKAs)

• the cell has multiple isoforms of PKAs

• the PKA then phosphorylates another downstream kinase as its target

• these kinases can vary from cell type to cell type and also vary according to the upstream ligand– epinephrine binding activates PKA - activates GPK (glycogen

phophorylase kinase)– insulin activates PKA which then activates acetyl CoA carboxylase

and then pyruvate dehydrogenase

cAMP Second Messenger systems

different effects of cAMP in different cells is due to the different effects of cAMP in different cells is due to the kinase cascade that PKA startskinase cascade that PKA starts

IP3 and DAG – Calcium as a second messenger• most intracellular calcium stores are

sequestered in the ER or other vesicles

• RTK or GPCR pathways trigger the activation of Phospholipase C/PLC – located in the plasma membrane

• PLC breaks down a phospholipid called PIP2

• results in production of inositol triphosphate/IP3 and diacylglycerol/DAG– IP3 diffuses through the cytoplasm and

activates Ca2+ channels on the ER - release of calcium within the cytoplasm

– IP3 can also open these channels in the PM and allow Ca2+ to diffuse in

– increased cytoplasmic calcium activates a class of calcium-dependent kinases called PKCs (protein kinase C) – role for DAG in this step

– PKCs then activate kinase cascades

Phosphorylation of substrates

http://bcs.whfreeman.com/lodish5e/content/cat_010/13010-01.htm?v=chapter&i=13010.01&s=13000&n=00010&o

Water soluble hormones and RTKs

• bind to protein/peptide classes of hormones and growth factors

• Receptor is called a receptor-tyrosine kinase/RTK

• signal binding leads to dimerization of the RTK

• this activates the RTK• activated RTK binds and

activates several “adaptor proteins”

• adaptor protein’s job is to activate Ras (GTPase)

• this activated Ras then activates multiple downstream kinase cascades

• the major one is called the MAPK pathway

Growth factorsPeptide hormones

• hormones can utilize more than one receptor and more than one pathway to activate the same target

– e.g. can bind and activate both GPCRs and RTKs

• allows two hormones to combine to increase the strength of an event

• or allows one hormone to decrease the cells response while the other hormone is trying to increase it

Water-soluble Hormone Signaling: Mechanisms