Question
proteins, peptides, amino acids, nucleotides, steroids, fatty acid derivatives, or gas
Signal
molecules can be _____, _____, _____, _____, _____, _____, or _____ ---
but they rely on only a handful of basic styles of communication for
getting the message across.
1)
Endocrine: hormones produced in endocrine cells are secreted into the
bloodstream & are distributed widely throughout the body.
2)
Paracrine: signals (acting as local mediators) are released by cells
into the extracellular fluid in their neighborhood & act locally.
3) Neuronal: neuronal signals transmitted along axons to remote target cells (via neurotransmitters)
4)
Contact-dependent: a membrane-bound signal molecule on the signaling
cell binds directly to a receptor protein on the target cell.
What are the 4 major ways that animal cells can signal to one another (communicate)? Briefly describe each.
-For a heart muscle cell: causes decreased rate & force of contraction
-For a salivary gland cell: causes secretion
-For a skeletal muscle cell: causes contraction
Different
types of cells respond to the same signal in different ways. Give an
example of this for the neurotransmitter acetylcholine.
What accounts for 20% of plasma membrane mass?
receptor proteins; working in combinations; fate
Every
cell type displays a set of _________ that enables it to respond to a
specific set of extracellular signal molecules produced by other cells.
These signal molecules regulate the behavior of the cell by
_________________. This is what controls cell _____ (i.e. whether the
cell will survive, die, grow & divide, differentiate, etc).
increased cell growth & division; slowly (mins to hrs); more quickly (< sec to mins)
Certain
types of cell responses -- such as _______________ -- involve changes
in gene expression & the synthesis of new proteins; they therefore
occur relatively _______. Other responses -- such as changes in
________, ________, or ________ -- need not involve changes in gene
expression & therefore occur _______.
1) large/hydrophilic; cell-surface receptors
2) small/hydrophobic; intracellular enzymes; intracellular receptors
Extracellular
signal molecules generally fall into 2 classes: 1) (largest class)
consists of molecules that are _______ or _______ and cannot cross the
plasma membrane of the target cell. They rely on ____________ to relay
their message. 2) (smaller class) consists of molecules that are
________ or ________ and can easily slip across the plasma membrane.
Once inside, they either activate _________ directly or bind ________ in
the cytoplasm or nucleus.
steroid hormones; cholesterol
One
important class of signal molecules that rely on intracellular receptor
proteins is the ________ ________ --- including cortisol, estradiol,
& testosterone --- which are made from ________.
These
hydrophobic molecules pass through the the plasma membrane of the
target cell & bind to receptor proteins located in the cytosol or
nucleus (collectively called nuclear receptors). Upon hormone binding,
the receptor undergoes a large conformational change that activates the
protein, allowing it to promote or inhibit transcription of specific
target genes. (note: receptors in the cytosol must move into the nucleus
and bind to the regulatory sequence in DNA, while receptors in the
nucleus are already bound to DNA).
Briefly describe how steroid hormones act as signal molecules in cells. (generalize)
B/c
it is quickly converted to nitrates & nitrites (half life of ~ 5-10
seconds) by rxn with oxygen & water outside cells.
Why does NO only work locally?
Inside
many target cells, NO binds to & activates the enzyme _______
_______, stimulating the formation of cyclic GMP from GTP. Cyclic GMP
forms the next link in the NO signaling chain that leads to the cell's
ultimate response. The drug ________ blocks the enzyme that degrades
cyclic GMP (cGMP-specific phosphodiesterase), prolonging the NO signal.
acetylcholine; endothelial; arginine; smooth muscle; proteins
Sequence
of events leading to dilation of a blood vessel: ___ is released by
nerve-terminals in the blood vessel wall & then diffuses to reach
receptors on the surface of the ______ cells lining the blood vessel.
There, it stimulates these cells to make NO from _____ & release it.
NO diffuses into adjacent ______ cells where it regulates the activity
of specific ______, causing muscle cells to relax.
1) relay
2) amplify
3) integrate
4) distribute
The
components of intracellular signaling pathways (proteins or small
messenger molecules; collectively called 'intracellular signaling
molecules') perform one or more crucial functions. Name 4.
1)
proteins that are activated (or inactivated) by phosphorylation; ex: P
added covalently by a protein kinase that transfers the terminal P group
from ATP to the signaling protein, turning it "on". protein phosphatase
then removes the P, turning it "off".
2) GTP-binding proteins; ex:
induced to exchange its bound GDP for GTP which turns it "on".
Hydrolysis of the bound GTP to GDP then switches the protein "off".
Proteins that act as molecular switches fall mostly into one of two classes. What are they? Give an example of how each works.
1) ion-channel-coupled
receptors
2) G-protein-coupled receptors
3) enzyme-coupled receptors
Cell-surface receptors fall into 3 basic classes. What are they?
ion-channel-coupled; G-protein-coupled
Some
signal molecules bind to receptors in more than one class. For example,
the neurotransmitter acetylcholine acts on skeletal muscle cells via a
_____________ receptor, whereas in heart muscle cells it acts through a
______________ receptor. (generate different intracellular signals &
thus enable the 2 types of muscle cells to react to acetylcholine in
different ways: contraction in skeletal muscle & relaxation in heart
muscle).
G-protein-coupled receptors have ___ transmembrane domains.
All
G proteins have a similar general structure. They are composed of ___
protein subunits (name them here) two of which are tethered to the
plasma membrane by short lipid tails (name these 2 here). In the
unstimulated state, the ___ subunit has GDP bound to it, & the G
protein is idle.
Binding
of an extracellular signal to the GPC receptor changes the conformation
of the receptor which in turn alters the conformation of the bound G
protein. The alteration of the α subunit allows it to exchange its GDP
for GTP. This exchange triggers a conformational change (α subunit
thought to detach from βϒ complex) that activates both the α subunit
& the βϒ complex, which can now interact w/ their preferred target
proteins/ion channels in the plasma membrane.
Briefly describe the general activation method of G proteins.
When
an activated α subunit binds its target protein, it activates (or
deactivates) the protein for as long as the 2 remain in contact.
**Within seconds, the α subunit hydrolyzes its bound GTP to GDP. This
loss of GTP inactivates the α subunit, which dissociates from its target
protein & it reassociates with the βϒ complex to re-form an
inactive G protein.
Briefly describe the general inactivation mechanism of G proteins.
enzymes or ion channels
The target proteins recognized by G-protein subunits are either ______ or ______ in the plasma membrane.
1) Binding of acetylcholine to its GPCR on heart muscle cells results in the activation of the G protein, Gi.
2)
The activated βϒ complex binds to & directly opens a K+ channel in
the plasma membrane, allowing K+ to flow out of the cell, decreasing the
cell's electrical excitability.
3) Inactivation of the α subunit by
GTP hydrolysis returns the G protein to its inactive state, allowing the
K+ channel to close.
Briefly describe how the heartbeat in animals is slowed down (by GPCR in heart muscle cells). 3 major steps.
adenylyl cyclase, cyclic AMP (cAMP);
phospholipase C; inositol trisphosphate & diacylglycerol;
signaling proteins
The
2 most frequent target enzymes for G proteins are ________, the enzyme
responsible for production of the secondary messenger (small
intracellular signaling molecule) _____, and ________, the enzyme
responsible for the production of 2 secondary messengers _____ &
_____. The signal is greatly amplified at this step b/c many secondary
messenger molecules are generated. They then diffuse to act on
intracellular _________.
adenylyl cyclase; cyclic AMP phosphodiesterase
Cyclic AMP is synthesized by ________ & degraded by ________________.
cyclic AMP-dependent protein kinase (PKA); serines or threonines
Cyclic
AMP exerts most of its effects by activating the enzyme _____________
(___). When activated, this enzyme then catalyzes the phosphorylation of
particular _______ or _______ on certain intracellular proteins, thus
altering the activity of the proteins.
The
hormone adrenaline binds to & activates a GPCR that turns 'on' a G
protein (Gs), which activates adenylyl cyclase. This boosts production
of cAMP. cAMP then activates PKA which phosphorylates & activates
phosphorylase kinase. This kinase phosphorylates & activates
glycogen phosphorylase which causes glycogen breakdown. (note: does not
involve changes in gene transcription/protein synthesis so occurs
rapidly).
Give a specific example of cAMP effect in the cytosol of skeletal muscle. (Describe whole process)
Adrenaline
binds & activates GPCR which turns 'on' a G protein (Gs), which
activates adenylyl cyclase. This boosts production of cAMP. In the
cytosol, cAMP then activates PKA which then moves into the nucleus &
phosphorylates specific transcription regulators. These TR proteins
then stimulate the transcription of a whole set of target genes. (note:
occurs slowly); hormone synthesis in endocrine cells to production of
proteins involved in long-term memory in the brain.
Give
an example of cAMP effect in the nucleus. This type of signaling
pathway controls many processes in cells ranging from
_____________________ to _____________________.
A
membrane inositol phospholipid is hydrolyzed by activated phospholipase
C, which produces 2 secondary messenger molecules. 1) Inositol
1,4,5-trisphosphate (IP3) diffuses through the cytosol & triggers
the release of Ca2+ from the ER by binding to & opening Ca2+
channels in the ER membrane. 2) Diacylglycerol remains in the plasma
membrane &, together w/ Ca2+, helps activate the enzyme protein
kinase C (PKC) recruited from cytosol to plasma membrane. PKC then
phosphorylates its own set of intracellular proteins.
Briefly describe what takes place when the enzyme phospholipase C is activated by an activated G-protein alpha subunit.
1)
Receptors with intrinsic enzyme activity (i.e. the cytoplasmic domain
of the receptor acts as an enzyme itself); ex: receptor tyrosine kinases
(RTKs)
2) Receptors without intrinsic enzyme activity (i.e. the
cytoplasmic domain of the receptor forms a complex w/ another protein
that acts as an enzyme); ex: prolactin receptor.
There are 2 classes of enzyme-coupled receptors. What are they? Give an example of each.
dimer; kinase; kinase; phosphorylates; tyrosines; interaction domain;
Typically,
the binding of a signal molecule to the extracellular domain of an RTK
causes 2 receptor molecules to associate into a _____. This brings the
_____ domains of each receptor tail into contact w/ the other,
activating their ____ function, w/ the result that each receptor ____
the other (on specific _____). This then stimulates the assembly of an
intracellular signaling complex of proteins that bind b/c they possess a
specialized ____ ____. These then help relay signal to cell's interior.
Virtually
all RTKs activate ______: a small GTP-binding protein (a monomeric
GTPase) that is bound by a lipid tail to the cytoplasmic face of the
plasma membrane.
An
adaptor protein docks on a particular phosphotyrosine on the activated
RTK. The adaptor then recruits a Ras-activating protein that stimulates
Ras to exchange its bound GDP for GTP, which activates it. (Ras can now
stimulate several downstream signaling pathways).
Briefly describe how a RTK activates Ras.
three-kinase; MAP kinase; transcription regulators; protein activity & gene expression
(consequence
of Ras activation): An activated Ras protein then activates a ___-___
signaling module, which relays the signal. The final kinase in the
module, ______, phosphorylates various downstream signaling or effector
proteins. These proteins can include other protein kinases &, most
importantly, _____ _____. The resulting changes in ____ & ____ lead
to complex change in cell behaviors such as proliferation &
differentiation.
The PI-3-kinase-Akt signaling pathway is important in regulating cell ______ & ______.
PI 3-kinase; phosphorylates; lipid docking sites; Akt (*also called PKB!); serines & threonines
An
extracellular survival signal activates an RTK, which recruits &
activates _____ which then ______ inositol phospholipids in the plasma
membrane. This then produces ____ ____ ____ in the plasma membrane that
attract intracellular signaling proteins . One of these signaling
proteins, ____, is a protein kinase activated by phosphorylation
mediated by 2 other protein kinases. Once activated, its released from
the plasma membrane & phosphorylates downstream proteins on specific
___.
A
growth factor binds to RTK which activates the
PI-3-kinase-Akt-signaling pathway . Akt then indirectly activates Tor
(note: by phosphorylating & inhibiting a protein that helps keep Tor
shut down). Tor (a serine/threonine kinase) stimulates protein
synthesis while inhibiting protein degradation which casues cell growth
(note: it does so by phosphorylating key proteins in these processes).Describe how Akt stimulates cells to grow.
The
prolactin receptor is associated with a specific pair of JAKs
(cytoplasmic tyrosine kinases). These JAKs first phosphorylate/activate
each other, & then phosphorylate the receptor proteins.
Transcription regulators called STATs bind to the receptor (where its
phosphorylated) & the JAKs phosphorylate/activate the STATs. STATs
disassociate, dimerize, & migrate to the nucleus where they help
activate the transcription of milk protein genes.