(Cell Bio Exam 3) Mechanisms of Cell Communication aka Cell Signaling

question

1 - C 2 - D

CQ part 2

B

What are secondary messengers responsible for

the amplification of the signal ATP--->cAMP GTP--->cGMP PIP2--->DAG PIP2--->IP3

There Are Three Major Classes of Cell-Surface Receptor Proteins what are they

(A) Ion-channel-coupled receptors (B) G-protein-coupled receptors, (C) enzyme-coupled receptors.

How do paracrine signals function

(B) Paracrine signaling depends on local mediators that are released into the extracellular space and act on neighboring cells.

How does synaptic signaling function

(C) Synaptic signaling is performed by neurons that transmit signals electrically along their axons and release neurotransmitters at synapses, which are often located far away from the neuronal cell body.

Protein peptide ligand

(insulin, epidermal growth factor) bind cell-surface receptors

Cell Communication involves what 2 important factors

(ligand and receptor) -a source cell or tissue that produces a signal (ligand) - a target cell or tissue with an appropriate receptor that binds the signal and undergoes a response *source and target*

explain slow response kinetics

(minutes/ hours) response transmitted to nucleus/ changes in gene expression --> synthesis of NEW proteins you have to assemble all of the components to make the proteins -synthesis of NEW effectors

explain fast response kinetics

(seconds/minutes) confines to cytoplasm, via changing activities of existing proteins -everything you need is already there they just need to be activated you don't have to make something new

G- protein couples receptors --allosteric system-

*allosteric changes*-there will be a conformational change in the protein as the ligand binds outside but there is a change in the shape of the protein intracellullarly

Nitric oxide is an relies on an _________receptor

*intracellular* ---> is a small molecule that can diffuse through the membrane ---NO is a local mediator as it is a gas an moved a short distance and can be perceived inside a cell

How does contact dependent signals function

Contact-dependent signaling requires cells to be in direct membrane- membrane contact.

CQ

D

CQ4

D

CQ 1

E

What are the 3 methods of transmitting signals across the membrane

1. ion channel 2. allosteric 3. dimerization

Small organic ligands

-Can diffuse through cell membranes to bind cytoplasmic/ nuclear receptors -steroids (estradiol, cortisol, testoserone) thyroxine, retinoids -signal synapses -amino acids (glycine, glutamate) and derivatives GABA

Low affinity receptors have a Kd around what

10^-6 (1uM)

High affinity receptors have Kd's around what

10^-9 (1 nM)

How does ligand binding to a receptor cause signaling within the cell (name 3 things)

1. Second messengers 2. Adaptor proteins and scaffolding proteins 3. Molecular switch proteins

How does an endocrine signaling function

D) Endocrine signaling depends on endocrine cells, which secrete hormones into the bloodstream for distribution throughout the body. Many of the same types of signaling molecules are used in paracrine, synaptic, and endocrine signaling; the crucial differences lie in the speed and selectivity with which the signals are delivered to their targets.

What is the delay that usually causes a slow response

E

Ion-channel-coupled receptors

Ion-channel-coupled receptors, also known as transmitter-gated ion channels or ionotropic receptors, are involved in rapid synaptic signaling between nerve cells and other electrically excitable target cells such as nerve and muscle cells.

What value measures the affinity of a receptor for a ligand

Kd Kd is also the concentration of free ligand (R) at which half the total receptor sites have bound ligand (RL) RT= R+RL

CQ 2

E--> The highest conserved portion-->Carboxy terminus (Ligand binding portion)---> amino terminus (NH2) The most conserved to the least conserved

What do interaction pathways ultimately do

Interaction domains enable signaling proteins to bind to one another in multiple specific combinations. Like Lego® bricks, the proteins can form linear or branching chains or three-dimensional networks, which determine the route followed by the signaling pathway.

Inorganic

NO (nitric oxide)

What are two main types of protein kinases

Protein kinases attach phosphate to the hydroxyl group of specific amino acids on the target protein. There are two main types of protein kinase. 1. serine/threonine kinases 2. tyrosine kinases

How do protein kinases ensure the specificity

Protein kinases, for example, contain active sites that recognize a specific amino acid sequence around the phosphorylation site on the correct target protein, and they often contain additional docking sites that promote a specific, high-affinity interaction with the target. These and related mechanisms help provide a strong and persistent interaction between the correct partners, reducing the likelihood of inappropriate interactions with other proteins.

Types of ligands

protein/ peptide small organic inorganic regardless of its chemical nature, the concentration of a ligand and its affinity for a receptor and the abundance of the receptor follow a universal relationship

What can bringing together signaling proteins do

Simply bringing intracellular signaling proteins together into close proximity is sometimes sufficient to activate them. Thus, induced proximity, where a signal triggers assembly of a signaling complex, is commonly used to relay signals from protein to protein along a signaling pathway. The assembly of such signaling complexes depends on various highly conserved, small interaction domains, which are found in many intracellular signaling proteins.

Which region is the *HALLMARK* the portion of the gene that is the same for each receptor

The Dna Binding region-- this region is highly conserved the same identical amino acid in each receptor protein (94% identical)

How are kinases named

The Kinase for phosphatidylinositols is always named after its substrate. (e.g. "PI Kinase" phosphorylates PI to make PI2. "PI2 Kinase" phosphorylates PI2 to make PI3.)

What region determines the identity of the receptor protein

The Variable region provides the receptor specificity for the ligand so in the variable region it provides uniqueness to the paticular ligand it will be interacting with (0)% conservation)-Nterminal End

Interaction Domains

The assembly of such signaling complexes depends on various highly conserved, small interaction domains, which are found in many intracellular signaling proteins. Each of these compact protein modules binds to a particular structural motif in another protein or lipid. The recognized motif in the interacting protein can be a short peptide sequence, a covalent modification (such as a phosphorylated amino acid), or another protein domain.

What does a binding of a signal to a cell surface receptor activate

The binding activates the receptor, which in turn activates one or more intracellular signaling pathways or systems. These systems depend on intracellular signaling proteins, which process the signal inside the receiving cell and distribute it to the appropriate intracellular targets. .

What do serine/ threonine kinases do

The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets.

What portion of the gene is partially conserved

The hormone binding domain (15-57% range of conservation) relatively conserved -C terminal End

What is the other important class of molecular switches

The other important class of molecular switches consists of GTP-binding proteins. These proteins switch between an "on" (actively signaling) state when GTP is bound and an "off" state when GDP is bound. In the "on" state, they usually have intrinsic GTPase activity and shut themselves off by hydrolyzing their bound GTP to GDP.

What are effector proteins

The targets that lie at the end of signaling pathways are generally called effector proteins, which are altered in some way by the incoming signal and implement the appropriate change in cell behavior examples of effector proteins -metabolic enzyme -transcription regulatory protein -cytoskeletal protei -ion channels

What are the two main types of GTP- binding proteins?

There are two major types of GTP-binding proteins. Large, trimeric GTP-binding proteins (also called G proteins) help relay signals from G-protein-coupled receptors that activate them. Small monomeric GTPases (also called monomeric GTP-binding proteins) help relay signals from many classes of cell-surface receptors.

What are second messengers

They are generated in large amounts in response to receptor activation and diffuse away from their source, spreading the signal to other parts of the cell. Some, such as cyclic AMP and Ca2+, are water-soluble and diffuse in the cytosol, while others, such as diacylglycerol, are lipid-soluble and diffuse in the plane of the plasma membrane. In either case, they pass the signal on by binding to and altering the behavior of selected signaling or effector proteins.

What is ion-channel couples receptors mediated by

This type of signaling is mediated by a *small number of neurotransmitters* that transiently open or close an ion channel formed by the protein to which they bind, briefly changing the ion permeability of the plasma membrane and thereby changing the excitability of the postsynaptic target cell.

What is a scaffold protein and what is its purpose

bring together groups of interacting signaling proteins into signaling complexes, often before a signal has been received. Because the scaffold holds the proteins in close proximity, they can interact at high local concentrations and be sequentially activated rapidly, efficiently, and selectively in response to an appropriate extracellular signal, avoiding unwanted cross-talk with other signaling pathways.

What are some specific second messengers

cAMP cGMP IP3 Ca2+

What are adaptor proteins and scaffolding proteins for

different domains function as docking sites for the binding of other proteins

Explain presence or absence of other signals

different pathways often show convergence or crosstalk

Enzyme coupled receptors -dimerization system-

dimerization--we will focus on receptor tyrosine kinase receptors---receptors are a dimer that does not contact until ligand binds connecting them outside leading to the dimerization of the protein inside

What do two inhibitory signals produce

A sequence of two inhibitory signals produces a positive signal

Does a signal molecule have the same effect on every target cell

A signal molecule often has different effects on different types of target cells. For example; Various responses induced by the neurotransmitter acetylcholin

When can NO response occur

An activated nerve terminal signals an acetylcholine release which subsequently turns arginine into Nitic Oxide using the activated NOS (nitric oxide synthase)---> diffusion to nearby cells occur to activate a response `

question 2

C - IP3 is an "activator" of releasing Ca2+ into the cytosol & ER ATPase is analogous to an "inactivator" due to reuptake mechanism of Ca2+

How is communication mediates in multicellular organisms

Communication between cells in multicellular organisms is mediated mainly by extracellular signal molecules

Scaffolding complex

Relay type structure that carries the signal down the protein

endocrine/ hormonal

long range communication

*Intracellular receptor* What are the different regions present on a gene that codes for a receptor protein

-Variable region (Transcription-Activating Domain) -DNA binding region -Hormone binding region (ligand binding domain)

What are the 3 big classes of cell surface receptors

getting information from the outside to the inside of the cell

Compare endocrine and synaptic signaling

-both allow signals to be delivered to LONG DISTANCE targets -endocrine relies on hormones binding specific receptors only found on target cells -synaptic signaling specificity depends on proximity and not necessarily the ligand (neurotransmitter)

The response to a given signal can vary depending on what 2 things

-cell history -presence or absence of other signals

What are the 4 modes of signaling between cells

-contact dependent -paracrine -neuronal (synaptic) -endocrine/ hormonal

What are the 4 ways extracellular signals can act

-contact dependent -paracrine -synaptic -endocrine

What are the speed or response of a cell signal

-fast -slow * a single signal can generate both fast and slow responses

explain how acetylcholine context matters

-heart muscle (decreases rate and force of contraction) -skeletal muscle (stimulate contraction) -salivary muscle (stimulate secretion)

What enzyme is necessary to make these secondary messengers

ATP--->cAMP *ENZYME; adenylyl cyclase* GTP--->cGMP *ENZYME; guanylyl cyclase* PIP2--->DAG PIP2--->IP3 *ENZYME; Phospholipase C*

Hormone receptors are transcription factors

Carrier proteins help small (hormone) ligands to stay in circulation and prevent the sticking/accumulation with other hydrophobic molecules in circulation.

Enzyme-coupled receptors

Enzyme-coupled receptors either function as enzymes or associate directly with enzymes that they activate. They are usually single-pass transmembrane proteins that have their ligand-binding site outside the cell and their catalytic or enzyme-binding site inside. Enzyme-coupled receptors are heterogeneous in structure compared with the other two classes; the great majority, however, are either protein kinases or associate with protein kinases, which phosphorylate specific sets of proteins in the target cell when activated

Extracellular Signals Can Act Over ______ or _____ Distances

Extracellular Signals Can Act Over Short or Long Distances

CQ3

Fast

Fast vs slow response image

Fast--> more day to day life components slow-->long term permanent changes

G Protein Coupled Receptor

G-protein-coupled receptors act by indirectly regulating the activity of a separate plasma-membrane-bound target protein, which is generally either an enzyme or an ion channel. A trimeric GTP-binding protein (G protein) mediates the interaction between the activated receptor and this target protein The activation of the target protein can change the concentration of one or more small intracellular signaling molecules (if the target protein is an enzyme), or it can change the ion permeability of the plasma membrane (if the target protein is an ion channel). The small intracellular signaling molecules act in turn to alter the behavior of yet other signaling proteins in the cell.

Crosstalk will inevitably occur; signaling molecules share the cytoplasm with a crowd of closely related signaling molecules that control a diverse array of cellular processes. It is inevitable that an occasional signaling molecule will bind or modify the wrong partner, potentially creating unwanted cross-talk and interference between signaling systems

How does a signal remain strong, precise, and specific under these noisy conditions? The first line of defense comes from the high affinity and specificity of the interactions between signaling molecules and their correct partners compared to the relatively low affinity of the interactions between inappropriate partners. The binding of a signaling molecule to the correct target is determined by precise and complex interactions between complementary surfaces on the two molecules.

What is the difference between transmembrane receptor activation and intracellular receptor activation

In most cases, receptors are transmembrane proteins on the target-cell surface. When these proteins bind an extracellular signal molecule (a ligand), they become activated and generate various intracellular signals that alter the behavior of the cell. In other cases, the receptor proteins are inside the target cell, and the signal molecule has to enter the cell to bind to them: this requires that the signal molecule be sufficiently small and hydrophobic to diffuse across the target cell's plasma membrane

In the G-protein coupled receptor response, what does the activated receptor serve as?

In the case of trimeric G proteins, the activated receptor serves as the GEF.

Modular Protein interaction allow the assembly of specific signaling complexes These domains are found on many genes

PH--Plextrin Homology and binds to IP3 in the plasma membrane SH3-- Sarc Homology Proline rich domains SH2--Sarc Homology binds to phosphorylated tyrosines PTB--Phosphotyrosine binding and it binds to phosphorylated tyrosine

PTB domain

Phosphorylated Tyrosine Binding --binds to phosphorylated tyrosines

What are the regulatory proteins that control these GTP- binding proteins

Specific regulatory proteins control both types of GTP-binding proteins. *GTPase-activating proteins (GAPs)* drive the proteins into an "off" state by increasing the rate of hydrolysis of bound GTP. Conversely, *guanine nucleotide exchange factors (GEFs)* activate GTP-binding proteins by promoting the release of bound GDP, which allows a new GTP to bind. In the case of trimeric G proteins, the activated receptor serves as the GEF.

SH2 domain

Src homology 2 (SH2) domains bind to phosphorylated tyrosines

SH3 domain

Src homology 3 (SH3) domains bind to short, proline-rich amino acid sequences

What are the two types of intracellular proteins that act as molecular swithces

Two types of intracellular signaling proteins that act as molecular switches. (A) A protein kinase covalently adds a phosphate from ATP to the signaling protein, and a protein phosphatase removes the phosphate. Although not shown, many signaling proteins are activated by dephosphorylation rather than by phosphorylation. (B) A GTPbinding protein is induced to exchange its bound GDP for GTP, which activates the protein; the protein then inactivates itself by hydrolyzing its bound GTP to GDP. OFF-SIGNAL

How does the DNA binding domain act as a transcription factor

When a ligand binds at the hormone binding domain it releases the inhibitor leading to a conformation change of the protein which ultimately acts as a transcription factor that can now interact with the gene for the gene to now be expressed to transcribe proteins. Inhibitor keeps the carboxyl tail in place and obscures the DNA-binding domain from associating with DNA.

When yeast communicate they produce a ______shape

When they communicate with each other using their mating factors they undergo a rapid and dramatic morphological change -when 2 haploid yeast form to form a diploid (sexual reproduction) then the shmoo forms -SHMOO

Does the maximum physiologic response require binding to all receptor sites

a Kd concentration of ligand does not need to occur *even one ligand can lead to an amplification signal*

What are some examples of intracellular signaling molecules

are proteins, which help relay the signal into the cell by either generating second messengers or activating the next signaling or effector protein in the pathway. Many of these proteins behave like molecular switches

Molecular switch proteins

are switched on by extracellular signals and then later switched off

Explain contact dependent

between adjacent cells whose proteins can bind to one another

paracrine

local signaling between neighboring cells- signal molecule has limited diffusion and/ or lifetime (cells in that immediate vicinity receive that signal )

Most cells in multicellular organisms both emit and receive signals. Reception of the signals depends on what

on receptor proteins

PH Domain

pleckstrin homology (PH) domains bind to the charged head groups of specific phosphoinositides that are produced in the plasma membrane in response to an extracellular signal

Explain cell history

results in cell intrinsic differences in receptor or " downstream" transduction machinery (ex variability of responses to acetylcholine)

neuronal (synaptic)

transmission can be long-range along axons but short range (paracrine) signaling synapses

How do tyrosine kinases function

tyrosine kinases which phosphorylate proteins on tyrosines. The two types of protein kinase are closely related members of a large family, differing primarily in the structure of their protein substrate binding sites.

What is a prominent place you see NO diffusion and why

you may see this in smooth muscle lining blood vessels because NO leads to vaso *dialation* nitroglycerin---> converts to NO---> vasodialation---> releasing the pressure This mechanism shows the communication between nervous system and muscular system

Regulators of G-Protein signaling (or RGS) proteins are important for what phase of signaling?

α-subunit hydrolyzes GTP GAPs that help out - RGS proteins: Regulators of G-Protein Signaling *Enhanced GTP hydrolysis in the Gα*