Lecture 11: Signal Transduction Flashcards Preview

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Flashcards in Lecture 11: Signal Transduction Deck (50):
1

Major categories of intercellular signaling:

- autocrine

- paracrine

- endocrine

- neural

- neuroendocrine

- pheromones

2

Local regulators

- moelcules acting over short distances

- reach target cells solely by diffusion

1. paracrine signaling

2. autocrine singlaing

3

paracrine

 

- target cells lie near the secreting cells

4

autocrine signaling

 

- target cells are also the secreting cells

5

endocrine signals

- 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

neural signals

 

- neurotransmitters released from neurons but are considered hormones because htey are carried by blood or other body fliuds and act on distant cells

7

pheromones

 

- released into the environment and act on a different individual

- serve many functions, including marking food trails, defining territories, and attracting potential mates

8

Main steps in a signal transduction pathway

 

1. reception - chemical signal is detected

2. transduction - chemical signal is converted to other chemical form

3. response - signal results in defined cellular activities

* signal transduction pathway always involves a chemical change from signal reception to actual cllular resosne

9

Common features of signal transducing system

 

1. specificity: binding of sinal molecule or ligand to a specific receptor

2. amplification: signal dependent enzyme cascade activation

3. desensitization/adaptation - feedback circuits can turn off signal-dependent activities

4. integration - ability to receive multiple signals and to produce a unified resposnse appropriate to the cellular needs

10

Specificity

 

signal molecule fits binding site on its complementary receptor; other signals do not fit

11

amplification

 

when enzymes activate enzymes, the number of affected molecules increases geometrically in an enzyme cascade

12

desensitization/adapters

 

- receptor activation triggers a feedback circuit that shuts off the receptor or removes it from the cell surface

13

integration

 

- 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

Quantification of Receptor-Ligand Interaction

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

Scatahcard analysis

- 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

Scatchard equations: unbound sites

 

 unbound sites = total sites - occupied: [R] = Bmax - [RL]

17

scatchard equations: equilibrium expression

 

Equilibrium expression:

Ka = [RL]/([L]{Bmax - [RL]}) = 1/kd

 

18

scatchard equations: ratio of receptor bound ligand to free ligand

 

[bound]/[free] = [RL]/[L] = Ka(Bmax- [RL]) = 9Bmax - [RL])/Kd

19

What are GPCRs?

 

- 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

biological functions mediated by GPCRs

 

- hormone action

- hormone secretion

- neurotransmission

- chemotaxis

- exocytosis

- control of BP

- embryogenesis

- cell growth and diff

- development

- smell, taste, vision

- viral infection

21

GPCR general structure

- 5th segment in interacts with G proteins

A image thumb
22

Activation of GPCRs

 

- 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

GPCR activation mechanism

 

24

on off switch of g proteins

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

 

A image thumb
31

insulin receptor tyrosine kinase

 

A image thumb
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)