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Biochem > Lecture 11: Signal Transduction > Flashcards

Lecture 11: Signal Transduction Flashcards

1
Q

Major categories of intercellular signaling:

A
  • autocrine
  • paracrine
  • endocrine
  • neural
  • neuroendocrine
  • pheromones
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2
Q

Local regulators

A
  • moelcules acting over short distances
  • reach target cells solely by diffusion
    1. paracrine signaling
    2. autocrine singlaing
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3
Q

paracrine

A
  • target cells lie near the secreting cells
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4
Q

autocrine signaling

A
  • target cells are also the secreting cells
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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)
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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
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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
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8
Q

Main steps in a signal transduction pathway

A
  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

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9
Q

Common features of signal transducing system

A
  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
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10
Q

Specificity

A

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

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11
Q

amplification

A

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

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12
Q

desensitization/adapters

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

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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
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16
Q

Scatchard equations: unbound sites

A

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

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17
Q

scatchard equations: equilibrium expression

A

Equilibrium expression:

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

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18
Q

scatchard equations: ratio of receptor bound ligand to free ligand

A

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

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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
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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
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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
Q

Regulation by cAMP dependent phosphorylation

A
26
Q

Epinephrine cascade in liver cells

A
27
Q

Sensory reception mediated by GPCRs

A
28
Q

G Protein GTPase and toxins

A
  • 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
Q

What are Receptor Tyrosine Kinases

A
  • 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
Q

RTK mechanism

A
31
Q

insulin receptor tyrosine kinase

A
32
Q

Insulin effect on glucose uptake

A
33
Q

Receptor Guanylyl cyclase

A
  • 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
Q

Structure of receptor guanylyl cyclase

A
35
Q

Gated ion channels

A
  • 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
Q

acatylcholine receptor

A
37
Q

adhesion receptors

A
  • 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
Q

Integrin in membrane

A
39
Q

nuclear receptors

A
  • 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
Q

How lipid soluble molecules regulate gene expression

A
41
Q

Estrogen and gene expresison

A
42
Q

Intracellular transduction processes

A
  • 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
Q

aplification via protein phosphorylation cascades

A
  • 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
Q

second messengers

A
  • 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
Q

cAMP

A
  • 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
Q

calcium ions

A
  • 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
Q

calcium ions mechanism

A
48
Q

Intracellular signal trasnduction

A
  • 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
Q

termination of inactivation signals

A
  • 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
Q

Cellular response to signals

A
  • 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)

Biochem (15 decks)

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