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Scientific Foundations > Lecture 19 > Flashcards

Lecture 19 Flashcards

Cell Signaling I

1
Q

types of intercellular signaling

A
  • direct signaling
  • paracrine signaling
  • endocrine signaling
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2
Q

direct signaling

A

direct connection between cells -> cells physically next to each other and touching through juxtacrine signaling (membrane proteins) OR signaling through gap junctions (channels) -> signaling is LOCAL and quick

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3
Q

paracrine signaling

A

molecules secreted by one cell and diffusing across to nearby molecules -> signaling is LOCAL; quick, but short-lived; autocrine (pain and inflammatory responses) and neuronal signaling (synapses)

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4
Q

endocrine signaling

A

slower, long-lived signaling; endocrine cells secreting hormones which have target cells all over the body -> travel via the vascular system (in the blood)

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5
Q

introduction of cellular signaling

A
  1. ligands (primary messenger -> signals) bind to the receptor
  2. signal transduction leads relay mechanism (cascade of events -> multi-step process -> receptor molecule goes through conformational change which leads cascade)
  3. cellular responses and/or changes in gene expression (could be short-lived, quick responses (proteins already made) or slower responses (proteins needing to be made))
  4. signal transduction can also lead to changes in gene expression
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6
Q

primary messengers

A

stimulus which send signals to receptors (ligands -> signal molecules, temperature, touch, sound, smell)

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7
Q

properties of cell signaling

A

True for ALL cell-signaling pathways
* specificity -> ligands bind to complementary receptor; specific receptors found only in specific tissues
* amplification -> sequence of signal cascades which activate many molecules
* modularity -> proteins have multiple domains, but only certain domains are recognized (domain activated by (de)phosphorylation) to cause certain signaling pathways
* desensitization/adaptation -> receptor activation triggers feedback pathway that shuts off receptor
* integration -> cells frequently receive multiple signals and combine/balance the two for its response
* localized response -> signaling mechanism localized within the cell

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8
Q

types of receptors and signaling pathways

A
  • G-protein coupled receptor
  • Receptor enzyme (tyrosine kinase) -> kinase activates transcription factor
  • Gated ion channel
  • Nuclear receptor
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9
Q

G protein-coupled receptor

A

external ligand binding to receptor activates an intracellular GTP-binding protein, which regulates an enzyme that generates an intracellular second messenger

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10
Q

receptor enzyme

A

receptor molecules act as enzymes when activated (like tryosine kinase)

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11
Q

gated ion channel

A

channel opens or closes in response to concentration of signal ligand or membrane potential (synaptic transmission)

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12
Q

nuclear receptor

A

common for steroid hormones -> hormones pass through membrane and lead to gene expression changes in the nucleus

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13
Q

G-protein coupled receptor signaling

A
  • ligand binding to GPCR (7 pass transmembrane receptor), extracellular domain, and intracellular domain
  • ligand binds in extracellular or transmembrane domain, conformational changes happen at intracellular domain to recruit G proteins
  • GDP bound to heterotrimeric unit, activated by GPCR and GDP replaced by GTP
  • Gsα releases and binds to another enzyme (usually adenylyl cyclase)
  • the 3 components are: 7 pass membrane receptor, use of G proteins, G proteins activating membrane bound enzyme
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14
Q

G proteins

A
  • 3 major G-proteins (typically heterotrimeric unit)
  • α, β, γ
  • called G-proteins because they bind to the guanosine nucleotide of GDP/GTP
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15
Q

epinephrine signaling

A
  1. epinephrine binds to its specific receptor (α1,α2,β1,β2 -> focus on β-adrenergic receptors) (transmembrane active site) -> induces conformational change
  2. hormone-receptor complex causes the GDP bound to Gsα to be replaced by GTP, activating Gsα
  3. Activated Gsα separates from Gsβγ, moves to adenylyl cyclase and activates it.
  4. Adenylyl cyclase catalyzes the formation of cAMP (second messenger) from ATP.
  5. cAMP activates PKA (protein kinase A)
  6. Phosphorylation of cellular proteins by PKA causes the cellular response to epinephrine.
  7. cAMP is degraded, reversing the activation of PKA
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16
Q

the GTPase switch

A
  • Gs bound to GDP -> GDP switched to GTP
  • Gs proteins are self-activating - intrinsically hydrolyzes the GTP to go back to GDP and inactivate
  • Gs can also use GAPs to inactivate
  • GDP-bound Gs incapable of activating adenylyl cyclase and needs to load a new GTP molecule
17
Q

cAMP as second messenger activates protein kinase A

A
  • PKA is a tetrameric molecule (2 regulatory subunits and 2 catalytic subunits) -> typically inactive
  • in the absence of cAMP, the R subunits bind tightly to C subunits and block activity
  • binding of cAMP to R subunits (conformational change) releases C subunits to phosphorylate their targets (substrates)
  • cAMP and PKA in dynamic equilibrium -> when conc decreases, R and C subunits bind
  • PKA adds phosphate groups to substrate/target protein
  • process goes back to cAMP
18
Q

amino acids that can take phosphate groups

A
  • serine, threonine, tyrosine
  • phosphorylation of serine or threonine common method of activating a target protein
19
Q

terminating GPCR signaling

A
  • mechanisms are only good if there are ways to stop them
    1. ligands themselves -> decrease in ligand concentration leads to receptor reassuming inactive conformation
    2. GTPase switch -> GDP bound to G proteins (hydrolysis of GTP)
    3. GTPase activator proteins (GAPs) -> stimulate GTPase activity causing more rapid inactivation of GTP
    4. cAMP hydrolyzed to 5’-AMP by cyclic nucleotide phosphodiesterase enzyme (so cAMP is inactive and so is PKA)
    5. PKA phosphorylating target proteins
20
Q

A-kinase anchoring protein

A
  • adaptor protein (A-KAP)
  • scaffold to bring downstream molecules together and anchor in one specific place -> for GPCR signaling to happen in a region
  • allows pathway to function as an assembly line complex
21
Q

Protein Phosphatase-2A (PP2A)

A

known component of the complex (GPCR pathway) -> yet another way to turn off signaling; PP2A slowly rips off the phosphoryl groups that were installed by PKA

22
Q

receptor desensitization/adaptation by β-ARK (β-adrenergic receptor kinase)

A
  1. as soon as Gsα departs, β-ARK rapidly binds to the β/γ subunits of the receptor and phosphorylates its intracellular “tail”
  2. β-ARK activated/phosphorylated by PKA
  3. creates a new docking site for another protein, β-arrestin (β-arr)
  4. β-arr then escorts the receptor into the cell by receptor-mediated endocytosis; decreases the number of receptors sitting in the membrane
  5. cells now have to adapt without the receptor
23
Q

inhibitory G proteins

A
  • not all GPCRs act by stimulating the G proteins -> some inhibit
  • Giα serve to inactivate adenylyl cyclase
  • analogous but opposite paradigm: receptor binding -> release of Giα -> inhibits adenylyl cyclase -> decrease [cAMP] -> decrease PKA activity
  • antagonists of Giα-coupled receptors will thus increase PKA activity
  • somatostatin inhibits glucagon secretion in pancreas through this mechanism
  • when epinephrine binds α2 adrenergic receptors, cAMP concentration decreases
24
Q

Gq-coupled receptor signaling

A
  • third major class of GPCRs (not activating or inhibiting)
  • seven-step process
    1. receptor binding
    2. GDP-GTP exchange and release of Gqα
    3. activation of phospholipase C
    4. cleavage of PIP2 by PLC into PIP3 and diacylglycerol (DAG) - 2 2nd messengers
    5. binding of IP3 to gated Ca2+ channel in ER membrane
    6. activation of PKC by Ca2+ and diacylglycerol (BOTH required)
    7. phosphorylation of numerous targets by PKC
25
Q

adrenergic receptors

A
  • α1 -> Gq
  • α2 -> Gi
  • β1, β2 -> Gs
26
Q

cellular calcium signaling

A

calcium is an important second messenger

27
Q

protein regulation by calmodulin

A

Ca2+ binds to adapter proteins
* calmodulin is a major Ca2+ binding protein in human cells
* protein is typically inactive at low [Ca2+], becomes active at high [Ca2+]
* calmodulin wraps around target proteins and usually activates them (for example - nitric oxide synthase)
* troponin is a cousin of calmodulin present in muscle cells -> activates tropmyosin

28
Q

GPCRs in vision

A
  • in rod and cone cells, light activates rhodopsin, which activates the G protein transducin
  • the freed α subunit of transducin activates a cGMP phosphodiesterase which lowers [cGMP] and thus closes cGMP-dependent ion channels in the outer segment of the neuron
  • the resulting hyperpolarization of the rod or cone cell carries the signal to the next neuron in the pathway
  • process: light activates rhodopsin -> rhodopsin recruits G proteins -> Tα-GTP activates cGMP phosphodiesterase (PDE) -> cation channels close, membrane hyperpolarized, signal to the brain -> rhodopsin kinase marks rhodopsin for recycling
29
Q

GPCRs in vision, olfaction, and gustation

A
  • in olfactory neurons, olfactory stimuli act through GPCRs and G proteins to trigger an increase in [cAMP] by activating adenylyl cyclase or [Ca2+] by activating PLC (calcium and sodium influx)
  • gustatory neurons have GPCRs that respond to tastants by altering levels of cAMP which changes the membrane potential by gating ion channels (potassium efflux)
  • vision, olfaction, and gustation in humans employ GPCRs which act through G proteins to change the membrane potential of a sensory neuron
30
Q

cholera toxin mechanism

A

external toxin modifying GPCR leading to diarrhea

  • Gsα always active -> opening of a lot of channels -> more water in the lumen
  • defective regulation of adenylyl cyclase and overproduction of cAMP
31
Q

epinephrine and synthetic analogs

A
  • epinephrine is released from adrenal gland and regulates energy yielding metabolism
  • isoproterenol is an agonist (similar function) with affinity higher than epinephrine -> used for treatment of acute bradycardia, heart block and shock
  • propanolol is an antagonist (blocks endogenous receptor activity) with extremely high affinity -> used for treatment of HTN, angina, cardiac arrythmia, thyrotoxicosis
32
Q

narcolepsy

A

disorder of orexin -> protein which signals for wakefulness
orexin is a GPCR

Scientific Foundations (46 decks)

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