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Cellular Neuroscience > Intracellular Signaling > Flashcards

Intracellular Signaling Flashcards

1
Q

G-Protein Coupled Receptors (GPCR)

A

detect photons
(light), hormones, growth factors, drugs, and other endogenous ligands

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2
Q

Monomeric G-proteins
or “small G-proteins”

A

belong to the
Ras superfamily of small GTPases (>100
proteins).
These proteins are homologous to the
alpha (α) subunit found in heterotrimers.

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3
Q

Heterotrimeric (“large”) G
-proteins

A

G-protein binds to the receptor

G protein is composed of 3 subunits (α, β, γ) *

the alpha subunit binds either to
guanosine triphosphate (GTP) or
guanosine diphosphate (GDP)
*

G proteins function as molecular
switches. They are “on” when they bind GTP, they are “off” when they bind GDP.

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4
Q

There are several classes of Gα subunits:

A

Gαs(stimulatory),
Gαi/αo(inhibitory, or
other),
Gαq(→ PLC pathway)

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5
Q

Activation of Heterotrimeric G
-proteins

A

When a ligand binds to the receptor, a conformational change occurs in the receptor that allows the Gα subunit to
exchange GDP for GTP.

This exchange triggers the dissociation of the Gα subunit from the Gβγ dimer and the
receptor and it activates the subunit(s).

The Gα-GTP monomer and the Gβγ dimer can now modulate the activity ofother intracellular (effector) proteins

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6
Q

Termination of Heterotrimeric G-proteins

A

The Gα subunit eventually hydrolyzes the attached GTP to GDP through its own enzymatic activity, allowing it to re-associate with Gβγ, forming the “resting” G-protein.

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7
Q

RGS proteins

A

(Regulators of G protein signaling, also called GAPs - GTPase-Activating Proteins)
accelerate the hydrolysis of GTP to GDP, terminating G-protein activity.

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8
Q

The effector (e.g. adenylyl cyclase)

A

may also possess GAP activity, which helps deactivate the pathway

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9
Q

Two principal signal transduction pathways of G protein-coupled receptors:

A

the adenylyl cyclase – cAMP signal pathway (via Gαs
and Gαi),

the Phospholipase C signal pathway (via Gαq)

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10
Q

Adenylate Cyclase and cyclic AMP

Upon binding of the alpha subunit of the G-protein, the
effector protein adenylate cyclase catalyzes

A

the
conversion of ATP to 3’,5’-cyclic AMP (cAMP)
→ Gαs stimulates, while Gαi
inhibits

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11
Q

cAMP acts as

A

a second messenger by
interacting with and regulating other
proteins, such as protein kinase A

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12
Q

cAMP is hydrolyzed back to AMP by

A

phosphodiesterases (PDEs)

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13
Q

G-protein coupled receptors
(Gαq)

A

activate PLC.

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14
Q

PLC cleaves PIP2
into

A

inositol -1,4,5-triphosphate (IP3,
soluble) and diacylglycerol
(DAG, membrane bound).

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15
Q

IP3
stimulates the release of

A

calcium ions from the
endoplasmic reticulum

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16
Q

DAG is an activator of

A

protein kinase C (PKC).

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17
Q

The ER has two pharmacologically
different Ca2+ stores

A
  1. activated via IP3 metabolism (PLC),
  2. elevation of cytosolic Ca2+ itself (Ryanodine-store)
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18
Q

Calcium stores

Mitochondria act as a

A

slow Ca2+ buffer
(MCU, mitochondrial calcium uniporter)

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19
Q

Internal calcium regulates:

A

the gating and kinetics of voltage-gated channels
* the gating and kinetics of ligand-gated channels
* Second messenger activation
* Protein kinases and phosphatases
* Gene expression

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20
Q

Molecular targets of signal transduction

Phosphorylation

A

addition of phosphate group to a molecule, usually a protein.

21
Q

Protein Kinases

A

enzymes that are the effectors of phosphorylation and catalyze the transfer of a phosphate group from ATP to specific amino acids on proteins.

22
Q

Proteins are phosphorylated predominantly on

A

Serine, Threonine and Tyrosine residues,
which account for 86, 12 and 2% respectively of the phosphoproteome
→ Serine/Threonine kinases, e.g. PKA, PKC or CaMKII
→ Tyrosine Kinases

23
Q

Protein Phosphatases

A

– enzymes that cleave phosphate from target molecule
→ dephosphorylate.

act inopposition to protein kinases

Can be grouped into three main classes based on sequence, structure and catalytic
function.

24
Q

General mechanisms of protein kinase
activation:

A

catalytic subunits
regulatory subunits (autoinhibition)
Binding of the second messenger

25
Q

catalytic subunits

A

responsible for
transferring phosphate groups to
target proteins

26
Q

regulatory subunits (autoinhibition)

A

catalytic subunits are being kept
inactive by

27
Q

Binding of the second messenger (cAMP; DAG; Ca2+)

A

removes
autoinhibition and allows catalytic
domain to be activated

28
Q

When the concentration of cAMP rises

A

cAMP binds to the
binding sites on the 2 regulatory subunits, which leads to the
release of the catalytic subunits

29
Q

Downregulation of PKA occurs by

A

a feedback mechanism: One of the substrates that
are activated by the kinase is a phosphodiesterase (PDE).
PDE converts cAMP to AMP, thus reducing the amount of cAMP that can activate
protein kinase A.
In addition, the catalytic subunit itself can be down-regulated by phosphorylation.

30
Q

Direct protein phosphorylation

A

PKA directly either
increases or decreases the activity of a protein (e.g. an
ion channel) → shown right

31
Q

Protein synthesis

A
  • PKA phosphorylates specific proteins
    (CREB) that bind to promoter regions of DNA, causing
    increased expression of specific genes. In general, this
    mechanism lasts longer (hours to days).
32
Q

DAG causes PKC to move
from the cytosol to the
membrane where it

A

binds
Ca2+ and another
phospholipid (PS).

33
Q

Calcium

A

binds to calmodulin

34
Q

Ca2+/calmodulin activates CaMKII by

A

displacing the inhibitory domain from the
catalytic subunit

35
Q

Calmodulin, or CaM

A

calcium sensor and signal transducer.
make use of the calcium stores in the endoplasmic reticulum

36
Q

As a result of the new protein synthesis, the synaptic actions are…

A

Prolonged; Closure of the channel and changes in neuronal ecitability last days or longer

37
Q

Mitogen-activated protein kinases (MAPK)

A

– including the extracellular signal-regulated kinase (ERK) subfamily -
phosphorylate transcription factors (proteins that regulate gene expression, e.g. CREB)

kinases that themselves are activated by other kinases

Growth factors –>Ras (GTP-binding proteins) –> Raf/Mapkkk –> Mek/Mapkk –> ERK/MAPK –> Proliferation, Deifferentiation, Cell survival

38
Q

Molecular mechanisms of early LTP

A

Rise in postsynaptic Ca2+
(through NMDARs)
→ acts as second messenger
At least 2 Ca2+
-activated protein kinases:
* Ca2+/calmodulin-dependent
protein kinase II (CaMKII), and
* Protein kinase C (PKC)
Expression (maintenance) of LTP is
typically due to insertion of AMPA-Rs into
the postsynaptic membrane
→ increased response to glutamate

39
Q

TrkB-stimulated intracellular signaling is

A

critical for neuronal survival,
morphogenesis, and plasticity.

40
Q

Binding of BDNF to TrkB elicits
various intracellular signaling
pathways:

A

1) phosphoinositide 3-kinase
(PI3K) pathway
2) phospholipase-Cγ (PLCγ)
3) mitogen-activated protein
kinase/extracellular signalregulated protein kinase
(MAPK / ERK)

41
Q

The amount of protein present in cells is determined by

A

the rate of
transcription of DNA into RNA

42
Q

Transcription factors

A

allow
RNA polymerase to assemble on
the DNA promoter region
and to begin transcription

43
Q

Transcription factors either

A

stimulate or inhibit
RNA polymerase activity

44
Q

Transcriptional Activators

A

enhance gene expression.

45
Q

Transcriptional Repressors

A

decrease gene expression.

46
Q

CREB (cAMP response element-binding protein)

CREB is a cellular transcription factor.
It binds to

A

DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the downstream genes.

47
Q

CREB is normally unphosphorylated. Its phosphorylation

A

potentiates transcription
(→ transcription requires binding of a co-factor to CREB and the RNA polymerase)

48
Q

Activators of CREB:

A
  • PKA
  • Ras / MAPK pathway
  • CaMK-IV (a variant of CaMK-II)
  • Ca2+

Cellular Neuroscience (10 decks)

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