Cell to cell communication Flashcards

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1
Q

Categories of chemical signaling (4)

A

Free diffusion: adjacent or distant
Cell signal to itself
Cell to cell contact

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2
Q

The adjacent cell communication is in

A

With the interstitial space

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3
Q

Extracellular signaling can (5)

A
  1. Coordinate the aggregation of movement of cells
  2. Initiate control under certain environmental conditions
  3. alter gene expression
  4. control metabolic processes between cells
  5. Contribute to nerve conduction
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4
Q

What metabolic processes can the extracellular signaling control (2)

A

Synthesis and secretion of proteins

Composition of intracellular and extracellular fluid

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5
Q

Types of signal molecules (4)

A

Small lipophilic molecules
Small hydrophobic molecules from a.a.
Gases
Physical stimuli (light)

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6
Q

What is a ligand

A

A signaling molecule

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7
Q

What does reception mean

A

Molecule to molecule contact

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8
Q

The target cell action depends on (4)

A

Signals that are present
Receptors that the target cell expresses on surface or IC
Signaling cascades
IC targets

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9
Q

What does ligand do

A

Bind together

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10
Q

What is a ligand

A

Molecule that binds to specific molecule called receptor

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11
Q

What is needed in order to detect a signal

A

The receiving cell must have the right receptor for that signal

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12
Q

What happens when a signaling molecule binds to a receptor

A

Alters the shape and activity of the receptor causing a change in the cell

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13
Q

T or F

A specific ligand with have a specific receptor that can bind to other ligands

A

False

Receptors are specific for one ligand

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14
Q

Types of ligands (2)

A

Those that enter the cell

Those that bind to receptors outside of cell

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15
Q

Properties of ligands(3)

A

Hydrophobic
Lipophilic
Can pass through membrane and bind to IC receptros in the nucleus or cytoplams

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16
Q

What type of ligand can directly travel across the membrane due to its small size

A

Nitric oxide (NO)

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17
Q

What is the key role of nitric acid as a ligand

A

Activate a signaling pathway in the smooth muscle surrounding blood vessels

Can make a muscle relax and blood vessels expand (dilate)

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18
Q

Properties of water soluble ligands (3)

A

Polar or charged
Cannot pass or cross the PM
Bind to extracellular domains of cell surface receptors staying on the outer surface

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19
Q

Example of water soluble ligand

A

Peptide protein ligands such as insulin and certain neurotransmitters

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20
Q

Different types of neurotransmitters (4)

A

Some are peptides
Other small hydrophilic organic molecules
Standard a.a.
Modified or non standard

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21
Q

What peptides are neurotransmitters(2)

A

Oxytocin

Endorphin

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22
Q

What types of hydrophilic molecules are neurotransmitters

A

Monoamines such as dopamine

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23
Q

What standard a.a. are neurotransmitters (2)

A

Glutamate and glycine

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24
Q

Examples of ligand (6)

A
Steroid hormones
Growth factors and hormones
Neurotransmitters
Nitric oxide
Light or photo transduction
Pressure or mechanotransducyion
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25
Q

Types of receptors (2)

A

Internal

Cell surface receptors

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26
Q

Internal receptors are where

A

IC and in the cytoplasm of the cell

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27
Q

Internal receptors respond to what type of ligand

A

Hydrophobic ligand that can travel across the PM

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28
Q

Ligand-binding causes

A

A conformational change that exposes the DNA binding site on protein

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29
Q

What causes the initiation of transcription and gene expression in a cell

A

When the ligand receptor complex moves into the nucleus and binds into a specific regulatory region of chromosomal DNA

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30
Q

T or F
With the internal receptors after the ligand has binded to the receptor and moved in the nucleus, you need other types of receptors and signals.

A

False

No need

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31
Q

What are the cell surface receptors

A

Membrane anchored (integral) proteins that bind external ligand molecules

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32
Q

What are the cell surface receptors also called

A

Transmembrane receptors

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33
Q

What do the cell surface receptor do to the PM

A

Spans it and produce a signal transduction in which EC signal is converted into IC signal

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34
Q

Main components of the cell surface receptors (3)

A

External ligand binding domain
Hydrophobic membrane spanning region
IC domain inside cell

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35
Q

Autocrine signals are produced by

What does that mean

A

Signaling cells that can also bind to the ligand that is released

Meaning that signaling cells and target cells can be the same or similar

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36
Q

Autocrine signaling can (2)

A

Regulate inflammation and pain responses

Signal apoptosis when the cell is infected by a virus

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37
Q

T or F

Abnormal autocrine signaling contributes to uncontrolled growth of cells such as cancer cells

A

True

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38
Q

Endocrine signaling are

A

Signals from distant cells originated from endocrine cells

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39
Q

T or F

Endocrine signals can produce faster responses but have a short lasting effect

A

False
Slower response
Long lasting effect

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40
Q

Ligands released from the endocrine signals are called

A

Hormones

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41
Q

What are hormones

A

Signaling molecules that are produced in one part of the cell but affect other body regions

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42
Q

How can hormones travel to target cells

A

Through the blood stream

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43
Q

What happens to the hormones when they act on target cells

A

They get diluted and are present in low concentrations

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44
Q

Paracrine signaling examples

A

Synaptic signaling

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45
Q

What is synaptic signaling (2)

A

Nerve cells transmit signal

Process named for the synapse, the junction between two nerve cells where signal transmission occurs

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46
Q

Types of cell to cell connections (4)

A

Tight junctions
Adherence junctions
Desmosomes
Gap junctions

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47
Q

Tight junctions

A

Seal the adjacent epithelial cells in a narrow band

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48
Q

Where can i find a tight junction

A

In lung epithelium

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49
Q

Adherence junctions

A

Provide strong mechanical attachments between adjacent cells

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50
Q

Where can i see adherence junctions

A

Cardiac muscle

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51
Q

Desmosomes

A

Hold a cell tightly together by linking IC to the intermediate filament cytoskeleton

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52
Q

Gap junctions

A

Allow signaling between cells

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53
Q

How do animal cells connect between PM and neighboring cells

A

Gap junctions

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54
Q

In plants what is the connection between plasma M and other cells

A

Plasmodesmata

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55
Q

Stages of signaling (3)

A

Ligand binding
Transduction
Cellular response

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56
Q

What happens in transduction

A

Amplification and spreading across specific pathway

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57
Q

What happens in cellular response (4)

A

Gene transcription
Cell proliferation
Differentiation
Cell survival

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58
Q

T or F

Ligands cannot act in 2 or 3 of the cell to cell signaling

A

False they can

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59
Q

Example of a ligand acting in more than one cell signaling

A

Epinephrine
Acts as a neurotransmitter and systemic hormone
So paracrine and endocrine signaling

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60
Q

What protein hormone is synthesized as the exoplasmic part of plasma membrane protein that can bind and signal an adjacent cell by direct contact

A

Epidermal growth factor

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61
Q

T or F

Ligands exhibit versatility just like receptors

A

FALSE
Ligands show versatility for receptors but the receptor displays high specificity to that ligand

Meaning a ligand can bind to many receptors while the receptor can only bind to a specific ligand

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62
Q

T or F

The response to a chemical signal decreases when EC concentrations of signals increase

A

False

Increase when EC concentrations increase

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63
Q

The more EC ligands means

A

The more responses

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64
Q

Maximum cellular response happens when

A

Saturation is reached due to finite numbers of receptors

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65
Q

T or F

Chemical signals don’t need to compete for a receptor

A

False

If they have similar structures they will and can compete for the same receptor

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66
Q

Can the same receptor trigger a different response in a ligand

A

Yes

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67
Q

An example of a receptor that can have different effects on a ligand

Explain

A

Acetylcholine

Release from a neuron adjacent to a striated muscle will trigger contraction where as if it was adjacent to the heart muscle it will slow down the rate of concentration

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68
Q

Where is acetylcholine found

A

On surface of striated muscle cells, hear muscles, and pancreatic acinar cells

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69
Q

Effects of acetylcholine in pancreatic acinar cells

A

Triggers exocytosis of secretory granules that contain digestive enzymes

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70
Q

T or F

Different ligand-receptor complexes can induce the same cellular response in some cell types

A

True

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71
Q

Example of specific mediated responses from different hormone-ligand complexes

A

Activation of epinephrine and glucagon receptors in liver cells by binding to their respective ligands induces synthesis of cAMP (2nd messenger)

So effect is identical in liver

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72
Q

T or F
Ligands can be metabolized for other products, is an intermediate in cellular activity and has important enzymatic activity

A

False

I doesn’t do anything

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73
Q

What is the function of the ligand

A

Bind to the receptor

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74
Q

Classes of cell surface receptors (4)

A

G protein coupled receptors
Ion channel receptors
Tyrosine-kinase linked receptors
Receptors with intrinsic enzymatic activity

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75
Q

Examples of G protein CR (3)

A

Epinephrine
glucagon
Serotonin

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76
Q

Examples of ion channel receptors

A

Acetylcholine

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77
Q

Example of Tyrosine-kinase linked receptor (2)

A

Erythropoietin

Interferon

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78
Q

The name of classes of receptors refer to

A

The mechanism by which the receptors transform EC signals into IC ones

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79
Q

T or F
Cell surface receptors can make changes in the function of the cell without actually going inside the cell

Explain

A

True

Because they work/ interact with EC and IC signals

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80
Q

Ion channels receptors are also called

A

Ligand gated ion channel receptors

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81
Q

The conformational changed caused by ligand binding in the receptor (ion channel receptor)allows what type of ions to pass through (5)

A
Ca
K
Na
Mg
H
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82
Q

What ligands work mostly with ion channel receptors (2)

A

Neurotransmitter such as glutamate

Acetylcholine

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83
Q

Example of receptors with intrinsic enzymatic activity

Explain

A

Atrial naturetic protein

Binds to its receptor causing a reduction in blood volume
So a decreased in cardiac output and systemic blood pressure occurs
Lipolisis increases and renal sodium decrease

The overall effect is to counter increase in blood pressure and volume caused by the renin angiotensin system

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84
Q

Enzyme linked receptors lack

A

Lack intrinsic catalytic activity but ligand binding stimulates formation of a dimeric receptor

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85
Q

What happens to the dimeric receptor formed by the ligand bonding in enzyme linked receptors

A

Interacts and activates cytosolic protein-tyrosine kinases

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86
Q

When the ligand binds, it activates a signal transduction cascade, what is the first thing released from this

A

G protein coupled receptors

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87
Q

The activation of an enzyme by a G protein generates what

A

A specific 2nd messenger or modulates ion channel, changing the membrane potential

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88
Q

Which type of receptor is the largest family of cell surface receptors

A

G protein coupled receptors

89
Q

Speed of effect diverging effects (4)

A
Opening another channel via internal binding site
Increase or decrease transcription
Protein modification (phosphorylation included)
Other downstream effects
90
Q

GPCR regulate (4)

A

Hormone secretion in the pancreas/gluconeogenesis: glucagon
Platelet mediated blood clotting: thrombin
Blood pressure regulation: angiotensin II, epinephrine
Mood: serotonin

91
Q

Examples of GPCR (4)

A

EPINEPHRINE
ANGIOTENSIN II
SEROTONIN
GLUCAGON

92
Q

Structure of GPCR (4)

A

Seven hydrophobic transmembrane segments
EC amino terminus
IC carboxyl terminus TM receptor
Coupled inactive G protein bound to trimetic subunit (alpha, beta, gamma)

93
Q

There are importance differences between receptor categories in part due to

A

Speed of effect

Duration of effect

94
Q

When we talk about speed of effect, what happens when the ligand binds to an ion channel receptor

A

It opens the channel, so there is an immediate flow of ions inducing excitatory postsynaptic or inhibitory postsynaptic potentials

95
Q

When we talk about speed of effect, what happens when the ligand binds to the protein/enzyme linked receptor

A

Then a cascade of secondary messengers system occurs

96
Q

When we refer to the duration of the effect, what happens when the ligand binds to the ion channel receptor

A

They’re usually very quick in response

97
Q

When we refer to the duration of effect, what happens when the ligand binds to the protein enzyme linked receptor

A

Depending on the receptors they’re usually delayed

98
Q

Rapid responses in the organisms are mediated by (2)

A

Peptide hormones

Catecholamines such as epinephrine, norepinephrine, dopamine

99
Q

How long does the peptide hormone persist in blood before being degraded by blood and tissue proteases

A

Sec or mins

100
Q

Catecholamines are rapidly inactivated by

A

Different enzymes or taken by specific cells

101
Q

Signaling molecules and their receptors (5)

A

Steroid hormones and the steroid receptor superfamily
Nitric oxide and carbon monoxide
Neurotransmitters
Peptides hormones, neuropeptides and growth factors
Eicosanoids

102
Q

Examples of steroid receptors (4)

A

Steroid hormones
Vitamin D
Retinoic acid
Thyroid hormone

103
Q

Steroid hormones are

A

Small hydrophobic molecules that diffuse across the PM of target cells
Bins to IC receptors

104
Q

Steroid hormones function as

A

Transcription factors to direclty regulate gene expression in response of ligand binding

105
Q

Neurotransmitters are (2)

A

Small hydrophilic molecules

Carry signals between neurons or between neurons and target cells

106
Q

Neurotransmitters bind to

A

Ligand gated Ion channels

107
Q

Which one is the widest variety of signaling molecules in animals (3)

A

Peptide hormones
Neuropeptides
Growth factors

108
Q

Eicosanoids are

A

Class of lipids that function in paracrine and autocrine signaling

109
Q

Examples of receptors bind to enzymatic activity include (3)

A

Protein-tyrosine phosphatases
Protein-serine/threonine kinases
Guanylyl cyclases

110
Q

Tyrosine kinase ligand receptors are

A

Receptor for most growth factor

111
Q

Signal transduction cascades (3)

A

IC signaling pathways
Amplify message
Produce multiple IC signals for every one receptor that is bound

112
Q

Example of signaling cascade form an enzyme linked receptor

A

MAPK pathway

113
Q

T or F

MAPK communicate by adding phosphate groups to a neighboring cell protein which acts an on or off switch

A

True

114
Q

Which receptor is a transmembrane molecule that can open or close a channel that allows cations to travel in and out the cell

A

Inotropic receptors

115
Q

When to ionotropic receptors open up

A

When the ligand binds to the receptor

116
Q

Domains of ionotropic receptors (4)

A

Extracellular amino terminal domain (ATD)
EC ligand binding domain (LBD)
Four transmembrane domains (CTD)
IC carboxyl terminal domain

117
Q

Example of ionotropic receptor

A

Ionotropic glutamate receptor

118
Q

Ionotropic glutamate receptos allow the passage of

A

Na
K
Ca sometimes
In response to glutamate binding

119
Q

T or F

Ionotropic glutamate receptor regulate the majority of excitatory neurotransmission within the cell

A

True

120
Q

T or F

All ionotropic receptors produce excitatory postsynaptic current at the same speed and duration

A

False

At different speed and duration

121
Q

IGRs (ionotropic glutamate receptors) are found where

A

On the pre and postsynaptic cell membranes primarily between the CNS

122
Q

IGRs are divided into subfamilies according to affinities (3)

A

AMPA
NMDA
Kainate

123
Q

NMDA have an internal site for

A

Mg

124
Q

NMDA receptors are permeable to what molecule

A

Ca

125
Q

T or F

Metabotropic receptos have channels

A

False

126
Q

Metabotropic link to a small chemical called

A

G protein

127
Q

What happens when the metabotropic receptor activates the g protein

A

G protein activates 2nd messengers

128
Q

What is the function of the 2nd messenger

A

Go and activate other particles

129
Q

Example of metabotropic receptos

A

Glutamate

130
Q

T or F

Ionotropic ligands are degraded slower than metabotropic

A

False

Its faster so channel closes fast

131
Q

What type of second messenger is Involved in visual reception in vertebral eye

A

cGMP

132
Q

Which are the 2nd messengers(6)

A
cAMP
cGMP
Phospholipids 
Ca
IP3
DAG
133
Q

Metabolic functions controlled by hormone induced second messengers include (3)

A

Uptake and utilization of glucose
Storage and mobilization of fat
Secretion of cellular products

134
Q

T or F
Removal or degradation of a ligand or second messenger or inactivation pf the ligand or receptor does not cause any effect in the cellular response since these actions are a part of the signaling transduction

A

False

It terminates the cellular response to an EC signal

135
Q

The epinephrine receptor is coupled to _______ _____ via a ______ _________ that stimulates enzymatic activity.

What does this do to cAMP

A

Adenylyl cyclase
G protein
Increase the concentration of cAMP IC

136
Q

How does cAMP signals the breakdown of glycogen

A

So cAMPs effects are mediated by PKA which is a tetramer with 2 catalytic parts and 2 regulators.
cAMP will bind to the regulator site of PKA breaking the catalytic parts off.
This catalytic parts are active. And from this phosphorylates kinase are activated.
Phosphorylase kinase phosphorylates and activates glycogen phosphorylase which is then broken down into glycogen and glucose-1-phosphate

137
Q

What is GEF

A

Guanine nucleotide exchange receptor

138
Q

What does GEF do

A

Exchange GDT to GTP bound to the alpha subunit in the G protein

139
Q

The exchange of GDT to GTP triggers what in the G protein

A

The dissociation of alpha subunit from the beta-gamma subunits and the receptor as a whole

140
Q

G alpha s does what

A

Stimulation of cAMP

Is a cAMP dependant pathway

141
Q

Which one is the cAMP dependent pathway

A

Gas

142
Q

What is the cAMP dependent pathway used for

A

As transduction pathway for some hormones

143
Q

What hormones use the cAMP dependent pathway (8)

A
ACTH
TSH
LH
PTH
Calcitonin
Glucagon
hCH
Epinephrine
144
Q

ACTH

A

Stimulates synthesis and release of cortisol

145
Q

TSH

A

Stimulates and release of T4 (thyroid glands)

146
Q

LH

A

Stimulates follicular development in women

Spermatogenesis in men

147
Q

PTH

A

Increases Ca levels in blood

148
Q

Calcitonin

A

Decrease Ca levels in blood

149
Q

Glucagon

A

Stimulates glycogen breakdown in the liver

150
Q

hCG

A

Promotes cellular differentiation, apoptosis

151
Q

Epinephrine

A

Released by adrenalmedula during fasting state

Stimulates glycogenesis and actions of glucagon

152
Q

G alpha i does what

A

Inhibit cAMP

153
Q

What molecule uses Gai

A

Insulin

154
Q

G alpha q/11

A

Stimulates phospholipase c which cleaves PIP2 into IP3 and DAG

155
Q

What is the inositol dependent pathway

A

G aq/11

156
Q

The inositol dependent pathway serves for what hormones (5)

A
ADH
TRH
TSH
Angiotensin II
GnRH
157
Q

ADH

A

Vassopresin, induces synthesis and release of glucocorticoids

158
Q

ADH induces

A

Vasoconstriction

159
Q

TRH

A

Induces synthesis and release of TSH

160
Q

Angiotensin II

A

Aldoterstosterone synthesis and release

161
Q

GnRH

A

Synthesis and release of FSH and LH

162
Q

G alpha 12/13

A

Involved with the Rho family

Involved with the remodeling of cells and regulation of cell migration

163
Q

G alpha t is known as

A

Transducon

164
Q

Transducin is found where

A

In rod and cone photoreceptors of eye

165
Q

Transducin activates what

Which does what

A

Phosphodiesterase to break down cGMP

166
Q

In protein kinases what is the common sites of phosphorylation (3)

A

Serine
Threonine
Tyrosine

167
Q

Where are places where the protein kinases can be found besides in the receptor

A

In the cytosol or associated with PM

168
Q

What type of kinases do animals have (2)

A

Those directed toward tyrosine

Those directed to serine or threonine

169
Q

In protein synthesis PKA activates what

A

CREB which binds to cAMP response element

170
Q

What happens to the protein when CREB binds to the cAMP response elements

A

It alters the transcription and the synthesis of the protein

171
Q

Activated PKC are translocated to the PM by

A

RACK proteins

172
Q

T or F

PKC HAVE A SHORT TERM ACTIVATION

A

FALSE

IS LONG TERM ACTIVATION

173
Q

RTK is

A

Receptor tyrosine kinase

174
Q

What happens if a growth hormone binds to the EC domain of a RTK

A

Triggers dimerization

175
Q

Dimerization of RTK leads to (2)

A

Rapid activation of the proteins cytoplasmic kinase domains

The activated receptors then becomes autophorphorylated into specific IC tyrosine residues

176
Q

T or F

Each molecules of epinephrine activates only a single receptor which can activate many G proteins

A

True

177
Q

In animal cells, increase of cAMP activates transcription of specific target cells that contain a regulatory sequence called

A

CRE

cAMP RESPONSE ELEMEMNT

178
Q

PKA can phosphorylate the transcription factor called

A

CREB

179
Q

What mediates cAMP actions

A

PKA

180
Q

How does cAMP stops signaling

A

Degradation by phosphodiesterase

181
Q

T or F
Many of the odorant receptors in sensory neurons in the nose are G proteins CR that stimulate adenylyl cyclase leading to an increase in EC cAMP

A

False is in IC

182
Q

What messenger relaxes smooth muscles

A

cGMP

183
Q

Relaxation of vascular smooth muscles lead to

A

Vasodilation and increase of blood flow

184
Q

IP3 causes the release of

A

Ca

185
Q

Hydrolysis of PIP2 yields

A

DAG

IP3

186
Q

In electrically excitable cells of nerve and muscles, levels of cytosolic Ca are increased by opening of (2)

A

Voltage gated ca channels in pm

Ryanodine receptors in ER and SR

187
Q

Phorbol ester promote

A

Growth of tumos in animals

188
Q

Acetylcholine is degraded by

A

Cholinesterase in miliseconds

189
Q

What are decoy receptors

A

Cell surface receptors that bind the ligand but do not convey the signal onward in the pathway

190
Q

What happens if the ligand cannot be degraded or sequestrated

A

Then the target cell may be desensitized

191
Q

How does desensitization occur(3)

A

Inactivation of receptor (blocking its interaction with downstream signaling components)
Sequestering the receptor into endocytic vesicles
Degrading the receptors in lysosomes

192
Q

Activated GPCRs can be desensitized when

A

When they are phosphorylated by different protein kinases

193
Q

The phosphorylated GPCRs then bind to

A

Arrestin

194
Q

Can arrestin mediate endocytosis receptors?

A

Yes

195
Q

Homeostasis of Ca levels in the cytoplasm is maintained by (3)

A

Calcium-permeable channels
Transporters
ATPases

196
Q

Ca is required by a lot of proteins which in turn regulate (3)

A

Asexual and sexual development
Circadian clock
Protein folding

197
Q

What is the most common signaling pathway that increases cytoplasmic calcium concentration

A

Phospholipase C pathway

198
Q

PLC is activated by

A

Cell receptors including G proteins and tyrosine kinase receptors

199
Q

How is PLC activated (4)

A

PLC hydrolyzes PIP2 to form IP3 and DAG
DAG recruits PKC attaching it to the plasma membrane
IP3 diffuses to the ER and binds to an IP3 receptor which serves as a Ca channel and releases Ca
Ca binds to PKC activating it

200
Q

Depletion of calcium from the ER will lead to Ca entry from outside the cell. This occurs by activation of

A

Store operated channels

SOCs

201
Q

CRAC refers to

A

The inflowing Ca current that results after stored calcium reserves have been released

202
Q

CRAC means

A

Calcium restored activated Ca current

203
Q

CRAC protein 1 is a calcium selective ion channel that is encoded by

A

Orai 1

204
Q

In excitable cells, Ca is essential for regulating processes such as (5)

A
Exocytosis
Gene regulation
Cell growth and proliferation
Enzyme control
Apoptosis
205
Q

Ca as a second messenger functions for (6)

A
Muscle contraction
Cellular motility
Fertilization
Cell growth or proliferation
Neurogenesis
Learning and memory
206
Q

High levels of Ca in the cytoplasm can cause

A

Apoptosis in the cell

207
Q

Example of a Ca binding protein

A

Calmodulin

208
Q

Calmodulin is activated by

A

Ca when the concentration of cytosolic Ca increases

209
Q

Example of Ca/Calmodulin dependent protein

A

Myosin light chain kinase

210
Q

A transcription factor phosphorylated by CaM is

A

CREB

211
Q

T or F

LDL receptors are recycled through endocytosis

A

True

212
Q

Receptor mediated endocytosis in cell signaling

A

Implicated in transducing signals from the cell periphery to the nucleus

213
Q

Arresting binding to the receptos is involved in

A

Receptor desensitization

214
Q

Where are IC receptors found

A

In the cytoplasm of cell

215
Q

Ic receptors respond to

A

Hydrophobic ligands that are able to travel across the PM

216
Q

The IC ligand receptor complex move into the

A

Nucleus and binds to the chromosomal DNA

217
Q

T or F

For the IC ligand receptors you need several receptor signals for the transcription of the gene in nucleus

A

False

No more is needed

218
Q

IC receptors are also known as

A

Nuclear hormone receptors

219
Q

Which are the nuclear hormone receptors (4)

A

Steroid hormone
Thyroid hormone
Retinoid
Vitamin D