Lecture 11: Signal Transduction Flashcards
1
Q
Major categories of intercellular signaling:
A
- autocrine
- paracrine
- endocrine
- neural
- neuroendocrine
- pheromones
2
Q
Local regulators
A
- moelcules acting over short distances
- reach target cells solely by diffusion
1. paracrine signaling
2. autocrine singlaing
3
Q
paracrine
A
- target cells lie near the secreting cells
4
Q
autocrine signaling
A
- target cells are also the secreting cells
5
Q
endocrine signals
A
- hormones produced and secreted by specialized cells or discrete organs called glands and then carried between distant cells by blood or other body fluids
- endocrine signaling eg maintinas homeostasis, mediates rsponses to external stimuli, and regulates growth and development (programs)
6
Q
neural signals
A
- neurotransmitters released from neurons but are considered hormones because htey are carried by blood or other body fliuds and act on distant cells
7
Q
pheromones
A
- released into the environment and act on a different individual
- serve many functions, including marking food trails, defining territories, and attracting potential mates
8
Q
Main steps in a signal transduction pathway
A
- reception - chemical signal is detected
- transduction - chemical signal is converted to other chemical form
- response - signal results in defined cellular activities
* signal transduction pathway always involves a chemical change from signal reception to actual cllular resosne
9
Q
Common features of signal transducing system
A
- specificity: binding of sinal molecule or ligand to a specific receptor
- amplification: signal dependent enzyme cascade activation
- desensitization/adaptation - feedback circuits can turn off signal-dependent activities
- integration - ability to receive multiple signals and to produce a unified resposnse appropriate to the cellular needs
10
Q
Specificity
A
signal molecule fits binding site on its complementary receptor; other signals do not fit
11
Q
amplification
A
when enzymes activate enzymes, the number of affected molecules increases geometrically in an enzyme cascade
12
Q
desensitization/adapters
A
- receptor activation triggers a feedback circuit that shuts off the receptor or removes it from the cell surface
13
Q
integration
A
- when 2 signals have opposite effects on a metabolic characteristic such as the concentration of a second messenger x, or the membrane potential Vm, the regulatory outcome results from the integrated input from both receptors
14
Q
Quantification of Receptor-Ligand Interaction
A
R + L <–> RL
K+1 (forward)
K-1 (reverse)
Ka = [RL]/([R][L]) = K+1/K-1 = 1/Kd
Ka = association constant
Kd = dissociation
15
Q
Scatahcard analysis
A
- receptor-ligand binding is saturable
- as more ligand is added to a fixed amount og receptor, an increasing fraction of receptors is occupied by ligand
- scatchard analysis - both dissociatin constant Kd and the number of binding sites Bmax in a goven preparation
16
Q
Scatchard equations: unbound sites
A
unbound sites = total sites - occupied: [R] = Bmax - [RL]
17
Q
scatchard equations: equilibrium expression
A
Equilibrium expression:
Ka = [RL]/([L]{Bmax - [RL]}) = 1/kd
18
Q
scatchard equations: ratio of receptor bound ligand to free ligand
A
[bound]/[free] = [RL]/[L] = Ka(Bmax- [RL]) = 9Bmax - [RL])/Kd
19
Q
What are GPCRs?
A
- largest familt of cell surface receptors
- mediate various biological functions related to eg: cell growth and diff, tissue dev, embryogenesis, sensing
- have a common structure with 7 transmembrane helices (and are thus also called 7TM receptors)
- b-andrenergic receptor is an importan example
20
Q
biological functions mediated by GPCRs
A
- hormone action
- hormone secretion
- neurotransmission
- chemotaxis
- exocytosis
- control of BP
- embryogenesis
- cell growth and diff
- development
- smell, taste, vision
- viral infection
21
Q
GPCR general structure
A
- 5th segment in interacts with G proteins
22
Q
Activation of GPCRs
A
- indirectly through G (GTP-binding) proteins, enzymes that generate intracellular second messengers (such as cAMP)
- G proteins act as on/off switches
- inactive when GDP is bound and are active when GTP is bound
- binding of a signal to a GPCR induces the change
23
Q
GPCR activation mechanism
A
24
Q
on off switch of g proteins
A
25
Regulation by cAMP dependent phosphorylation
26
Epinephrine cascade in liver cells
27
Sensory reception mediated by GPCRs
28
G Protein GTPase and toxins
- bacterial toxins (such as cholera toxin and pertussis toxin) can modify G Proteins and hence inhibit their GTPase activity
- adenylate cyclase is always (constitutively) active and produces too much cAMP from ATP
29
What are Receptor Tyrosine Kinases
- dimeric receptors and ligand-binding to the extracellular domain of one subunit causes its intracellular domain to phosphorylate specific tyrosine residues in the other receptor subunit
- the resulting conformational changes dramatically increase the kinase activity of the receptor (dimer)
- the activated forms initiate a kinase cascade that includes lipid kinases and protein kinases
\* insulin receptor is an important example
30
RTK mechanism
31
insulin receptor tyrosine kinase
32
Insulin effect on glucose uptake
33
Receptor Guanylyl cyclase
- upon ligand-binding to these receptors, their cytosolic domains convert GTP to cGMP, which activates a protein kinase that phosphorylates cellular proteins and thereby changes their activities
- some are not mmebrane-bound such as the soluble NO-activated guanylyl cyclase (found in mny tissues, including smooth muscle of heart and blood vessels)
- atrial natriuretic factor ANF receptor (found in renal collective ducts and vascular smooth muscles) is an important example
34
Structure of receptor guanylyl cyclase
35
Gated ion channels
- plasma membrane receptors that open in rsponse to ligand-binding (or changes in trasnmembrane potential) and allow specific ions like Na+, K+ or Ca2 through a channel within these receptors
\*acetylcholine is important ex
36
acatylcholine receptor
37
adhesion receptors
- interact with defined macromolecular components of the ECM and convey instructions to the cytoskeletal system about cell migration or adherence to the matrix
-
\*integrin is good example
38
Integrin in membrane
39
nuclear receptors
- soluble (not membrane associated) and located either in the cytoplasm or nucleus
- respond to lipid-soluble ligands (steroids, thyroid hormones, and hormonal forms of vitamin D)
- ligand-receptor complexes then act as transcription factors in the nucleus, regulating transcription of specific genes (thereby changing gene expression patterns)
- the strogen-receptor is an important example
40
How lipid soluble molecules regulate gene expression
41
Estrogen and gene expresison
42
Intracellular transduction processes
- transduction processes occur within cells and usually involve multiple steps that can:
- amplify a signal: with only a few signal moleculas binding to specific receptors producing large cellular response (signal amplification)
- diversify or channel signals by allowing pathway branching and cross talk to generate a unified cellular response (signal integration)
- turn off or terminate signal dependent activities using feedback circuits (signal adaptation or desensitization)
43
aplification via protein phosphorylation cascades
- in many pathways, a signal is transmitted and amplified by a cascade of protein phosphorylation
- protein kinases transfer phosphates from STP to protein, a process called phosphorylation
- protein phosphatases remove the phosphates from proteins, a process called dephosphorylation
- phosph and dephosph system acts as a molecular switch, turning activities on and off, or up or down as required
44
second messengers
- extracellular signal molecule (ligand) that binds to the receptor is a pathway's first messenger
- second messengers are small, nonprotein, water soluble moelcules or ions that are produced in response to binding of extracellular ligands (first messenger) to specific receptors, spread throughout a cell by diffusion to participate in defined intracellular transduction
45
cAMP
- cAMP and calcium ions are common second messengers
- adenylyl cyclase converts ATP to cAMP in response to an extracellular signal, while cAMP phosphodiesterase converts cAMP into AMP
- many signal molecules trigger formation of cAMP by binding to GPCRs and activation of certain G proteins
- cAMP usually activates protein kinase A, which phosphorylates various other proteins
- further regulation of cell metabolism is provided by G protein systems that inhibit adenylyl cyclase
46
calcium ions
- act as potent second messengers in many pathways
- calcium is an important second messenger because cells can regulate its concentration
- a signal relayed by a signal transduction pathway may trigger an increase in cytocolis calcium (Ca2+)
- pathways leading to the release of calcium involve inositiol trisphosphate (IP3) and diacylclycerol (DAG) as an additional second messenger
47
calcium ions mechanism
48
Intracellular signal trasnduction
- different kinds of cells have different collections of proteins, which allow cells to detect and respond to different signals
- event the same signal can have different effects in cells with different proteins and pathways
- pathway branching and "cross talk" further help the cell to coordinate incoming signals
49
termination of inactivation signals
- termination or inactivation mechanisms are an essential aspect of cell signaling
- if a ligand concentration falls, fewer receptors will be bound. unbound receptors revert to an inactive state
- along a phosphorylation cascade phosphorylated proteins are dephosphorylated by protein phosphatases
- these mechanisms allow the cell to remain sensitive to small changes from reception to response of specific signals
50
Cellular response to signals
- ultimately a signal transduction pathway leads to regulation of one or more cellular activities
- many signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus (transcriptional regulation)
- final activated molecule in the singaling pathway may function as transcription factor
- other pathways regulate the activity of enzymes rather than their synthesis (post-trans reg)
