Molecular Signaling within Neurons Flashcards
Signal amplification across several steps in a cascade is _____.
exponential
Extracellular signaling molecules:
- Small soluble organic molecules e.g. Neurotransmitters, amino acids, sugars, nucleotides
- Inorganic ions (e.g. Zn2+)
- Diffusable gases (e.g. CO & NO)
- Peptides
- Lipophilic organic molecules (e.g. endocannabinoids)
- Cell-surface expressed proteins
Cholesterol derived hormones are ____ molecules.
cell permeant
Cell-cell adhesion molecules require _____.
direct contact
metabotropic receptors are proteins consisting of ___.
7 transmembrane domains
Domains _____ make up the neurotansmitter binding region of metabotropic receptors.
II, III, VI, and VII
G-proteins bind to both the loop between domains _ and _ and the _____.
V
VI
C-terminus
Ras are small ____.
GTPases
bind and accelerate hydrolyzation of guanosine triphosphate
Heterotrimeric G-proteins are “_____.”
large
There are several classes of Gα subunits:
G(s)α (stimulatory)
G(i)α (inhibitory)
G(q)α (activates phospholipase C)
Proteins called GTPase-activating proteins (GAPs) accelerate the _____.
hydrolisis of GTP to GDP
Monomeric G-proteins are known as “_____.”
small G-proteins
“Small” G proteins belong to the _____ of small GTPases.
Ras superfamily
Monomeric proteins are homologous to the _____ found in heterotrimers.
alpha (α) subunit
A small GTPase can function independently as a _____ to bind to and hydrolyze _____.
hydrolase enzyme
GTP to form GDP
Two principal signal transduction pathways of G protein-coupled receptors:
1) Adenylyl cyclase – cAMP signal pathway (via G(α-s) and G(α-i))
2) Phospholipase C signal pathway (via G(α-q))
Activation of adenylate cyclase (via G(s-α) or G(i-α) leads to:
- cAMP formation
* protein kinase A (PKA)
The adenylyl cyclase (cAMP signal) pathway through B-adrenergic GPCR _____.
increases protein phosphorylation
The adenylyl cyclase (cAMP signal) pathway through DA(2) GPCR _____.
decreases protein phosphorylation
The Phospholipase C signal pathway through mGluR _____.
increases protein phosphorylation
activates calcium-binding proteins
Upon binding of the alpha subunit of the G-protein, _____ catalyzes the conversion of ATP to _____.
adenylate cyclase
3’,5’-cyclic AMP (cAMP)
G(α-s) and G(α-i) oppose each other through their modulation of _____.
adenylyl cyclase activity
Binding of G(α-s) (via D1 receptors) to AC _____ the synthesis of cAMP.
increases
Binding of G(α-i) (via D2 receptors) to AC _____ the synthesis of cAMP
decreases
5-HT (via a metabotropic receptor) activates _____ which in turn increases cAMP, and then _____.
Adenylyl-cyclase
PKA
PKA has 2 effects:
- Closes K+ channels, leading to broader spikes and more Ca2+ influx (more transmitter release)
- PKA directly increases the release of neurotransmitter
G-protein coupled receptors (G(α-q)) activate _____.
PLC
PLC cleaves PIP2 into _____ and _____.
inositol -1,4,5-triphosphate (IP3, soluble)
diacylglycerol (DAG, membrane bound)
IP3 stimulates the release of _____ from the endoplasmic reticulum.
calcium ions
DAG is an activator of _____ which stimulates the release of calcium ions through a _____.
protein kinase C (PKC)
Ca2+ channel
Under baseline conditions, the cytosol is largely kept _____ of Ca2+
devoid
Ca2+ as a secondary messenger is either pumped out of the cell, sequestered in internal stores in the _____ and _____, or bound by _____.
ER lumen
mitochondrial matrix
calcium-binding proteins
_____ and _____ receptors in the ER membrane allow flow of Ca2+ from internal stores into the _____.
IP3
ryanodine
cytosol
As a messenger, Ca2+ targets:
Calmodulin
Protein kinases
Ion chennels
Synaptotagmin
cAMP (acronym):
Cyclic adenosine monophosphate
cAMP is synthezised from ATP by _____.
adenylyl cyclase
An increase in cAMP leads to activation of _____.
Protein kinase A (PKA)
Removal mechanism of cAMP
cAMP phosphodiesterase
Removal mechanism of IP(3)
Phosphatases
Protein Kinases
enzymes that are the effectors of phosphorylation and catalyze the transfer of a phosphate group from ATP to specific amino acids on proteins.
Proteins are phosphorylated predominantly on ______, _____, and _____ residues.
Serine
Threonine
Tyrosine
types of protein kinases
Serine/Threonine kinases
Tyrosine Kinases
Protein Phosphatases
enzymes that cleave phosphate from target molecule
dephosphorylate
_____ are responsible for transferring phosphate groups to target proteins.
Catalytic subunits
Catalytic subunits are being kept inactive by _____.
regulatory subunits (autoinhibition)
Binding of the second messenger (cAMP; DAG; Ca2+) removes _____ and allows ______ to be activated.
autoinhibition
catalytic domain
cAMP activates PKA by binding to the _____ and causing them to release active _____.
regulatory subunits
catalytic subunits
Catalytic subunits phosphorylate_____ and _____ of target proteins after activation.
serine
threonine residues
DAG (Diacylglycerol) causes _____ to move from the cytosol to the membrane where it binds ____ and another _____.
PKC
Ca2+
phospholipid (PS)
binding of _____ to PKC relieves autoinhibition, enabling PKC to phosphorylate proteins.
DAG
CaMKII (acronym):
Ca2+/calmodulin dependent protein kinase type II
On CaMKII, calcium binds to _____.
calmodulin
Ca2+/calmodulin activates CaMKII by displacing _____ from the _____.
the inhibitory domain
catalytic subunit
At least 2 Ca2+-activated protein kinases are responsible for LTP:
- Ca2+/calmodulin-dependent protein kinase II (CaMKII), and
* Protein kinase C (PKC)
Expression (maintenance) of LTP is typically due to insertion of _____ into the _____ membrane
(increasing the response to glutamate)
AMPA-Rs
postsynaptic
MAPK (acronym):
Mitogen-activated protein kinase
MAPK [specifically the extracellular signal-regulated kinase (ERK) subfamily]
Phosphorylate transcription factors
proteins that regulate gene expression
Late LTP is induced by changes in _____ and _____ brought about by the persistent activation of protein kinases activated during early-LTP, such as _____.
gene expression
protein synthesis
MAPK
Many signaling cascades involved in early-LTP, including CaMKII and PKC, can converge on _____.
ERK
Upon activation, ERK phosphorylates transcription factors such as _____, leading to _____.
CREB
synthesis of new proteins
Cascades can _____ at G-proteins to produce different effector proteins or _____ at effector/G-proteins to produce one kind of effector protein.
diverge
converge
______ are the primary effectors of dephosphorylation and act in opposition to ______.
Protein phosphatases
protein kinases
The largest class of ______ is the phosphoprotein phosphatase family, which –among others– contains __, __, and __.
PPs (protein phosphatases)
PP-1
PP-2A
PP-2B (calcineurin)
Several proteins have _____ for activating or inhibiting functional regulation.
separate phosphorylation sites
The amount of protein present in cells is determined by the rate of _____.
transcription of DNA into RNA
Transcription factors allow _____ to assemble on the _____ and to begin transcription.
RNA polymerase
DNA promoter region
Transcription factors either stimulate or inhibit _____ activity.
RNA polymerase
transcriptional activator protein
Transcriptional Activators
enhance gene expression
Transcriptional Repressors
decrease gene expression
CREB (acronym):
cAMP response element-binding protein
CREB is a _____.
cellular transcription factor
CREB binds to DNA sequences called _____, thereby increasing or decreasing the transcription of the downstream genes.
cAMP response elements (CRE)
CREB is normally _____.
unphosphorylated
CREB’s phosphorylation potentiates _____.
transcription
Activators of CREB:
- PKA
- Ras / MAPK pathway
- CaMK-IV (a variant of CaMK-II)
- Ca2+
Important genes transcribed by CREB:
- c-fos (an immediate early gene that itself acts as transcription factor for other genes)
- the neurotrophic factor BDNF
- tryosine hydroxylase
- neuropeptides
