Download Biochemistry Chapter 11 [10-2-13].

Biochemistry Chapter 11:
Cell Signaling by Chemical Messengers
I. Chemical Messengers
A. Signaling molecules
1. general sequence:
a. C.M. secreted by a specific cell in response to a stimulus
b. C.M. diffuses or transported to target cell
c. a receptor in the target cell binds to the C.M.
d. the binding elicits a response
e. signal ceases and terminated
2. ex. Acetylcholine (acts on nicotinic Ach receptor)
a. neurotransmitters secreted in response to electrical stimulus
(action potential) caused by changes in Na+ and K+ gradients
b. Ca2+ influx causes release of Ach into synaptic cleft
c. Ach binds to nicotinic Ach receptor
d. causes conformational change to allow influx of Na+ and efflux
of K+
e. acetylcholinesterase terminates (destroys Ach)
B. Transmit messages between cells
1. secreted from one sell in response to a specific stimulus and travel to a
target cell, where they bind to a specific receptor and elicit a response
2. In the nervous system, C.M.’s are called neurotransmitters
3. In the endocrine system, ---hormones
4. In the immune system, ---cytokines (small protein; 20,000 Da)
a. kill microorganisms
b. interleukins, interferons, tumor necrosis factors, ect.)
5. Additional messengers include:
a. retinoids (derivatives of Vitamins A & D; considered hormones)
b. eicosanoids (prostaglandins, thromboxanes, leukotrienes)
1. control cellular function in response to injury
2. paracrine or antocrine
c. growth factors
1. platlets aggregating at site of injury release PDGF
2. some considered hormones and some called cytokines
C. Depending on distance traveled, C.M.’s can be classified as:
1. endocrine (travel in blood) (ex. Insulin (secreted by B-cells of pancreas))
2. paracrine (travel between nearby cells) (ex. Ach)
3. autocrine (act of same cell or cell or on nearby cells of same type)
II. Receptors and Signal Transduction
A. Receptors are proteins that contain a specific binding site for a single C.M. and
another binding site involved in transmitting the message
1. second binding site may interact with another protein or DNA
2. can either be:
a. plasma membrane receptors
1. spans plasma membrane and contains an extracellular
binding domain for the messenger
a. also has 1 or more membrane-spanning domains
1. -helicies
b. also has intracellular domain for signal transd.
2. when ligand bindscauses conformational change
3. polar molecules-cannot diffuse across membrane
4. pathway of signal transd. Has 2 major effects:
a. rapid effects on ion levels or activation/inhibition
of enzymes
b. slower changes in the rate of gene expression
b. intracellular binding proteins
1. hydrophobic messengers
2. gene-specific transcription factors
3. steroid hormones, thyroid hormone, retinoic acid, vit. D
a. transported in blood bound to albumin
1. has hydrophobic binding site
b. intracellular receptors are very similar
1. called steroid hormone/thyroid hormone
superfamily of receptors
2. found in nucleus (sometimes cytoplasm)
B. Most plasma membrane proteins fall into one of the following:
1. Ion-channel receptors
a. nicotinic Ach receptor
b. ligand binding causes conformational change
2. Tyrosine kinase receptors
a. generally exists as monomer with single transmembrane helix
b. steps:
1. binding of ligand and dimerization
2. intracellular tyrosine kinase domains phosphorylate each
other on certain tyrosine residues (autophosphorylation)
3. one of the domains forms a binding site for an SH2
domain
4. Grb2 binds (has SH2 domain) to phosphotyrosine; causes
a conformational change in Grb2 called SH3 domain
5. SOS (GEF) binds
a. SOS--guanine nucleotide exchange factor for RAS
6. Ras binds
a. anchored to plasma membrane
b. monomeric G-protein
7. GEF activates the exchange of GTP for bound GDP on
RAS
8. conformational change on Ras lets Raf bind
a. Raf is a serine protein kinase
1. mitogen activated protein kinase k. k.)
2. MAPKKK
c. insulin receptor is similar except it exists as a dimer so it has
more SH2 binding domains
3. Tyrosine kinase-associated receptors (JAK-STAT receptor)
a. used by cytokines to regulate immune response
b. more direct route for propagation of signal to nucleus
c. the receptor itself has no intrinsic kinase activity, but it binds
with tyrosine kinase JAK
d. signal transducer is STAT
e. steps:
1. cytokine binds to the receptors; form dimmers
2. activated JAKs phosphorylate each other and intracellular
tyrosine residues on the receptor
a. forms phosphotyrosine binding sites for SH2
domain of STAT
3. STAT phosphorylated by JAK
4. The phosphorylation of STAT causes it to have a
conformational change, causing it to dissociate from the
receptor and dimerize with another STAT
5. The STAT dimer translocates to the nucleus
4. Serine-threonine kinase receptors
a. proteins in the transforming growth factor superfamily use
receptors that have a serine-threonine kinase activity and
associate with Smad proteins (always associated with serine-threonine
kinase receptors) (gene-specific transcription factors)
1. e.x.: TGF-, cytokine/hormone involved in tissue repair,
immune regulation, and cell proliferation
b. steps:
1. TGF- binds to a type II receptor
2. The activated type II receptor recruits a type I receptor
and phosphorylates its serine residue
3. The type I receptor binds to a receptor specific Smad and
phosphorylates its serine residues
4. The phosphorylates Smad dissociates and joins up with
another Smad (Smad4 or Co-Smad)
5. The new Smad dimer travels to the nucleus
5. Heptahelical receptors
a. named for their 7 membrane spanning domains (-helicies)
b. each receptor is specific for one peptide hormone or neurotransm.
c. no intrinsic kinase activity
d. initiate signal transduction through heterometric G-proteins
e. Steps:
1. G-protein is composed of 3 subunits and it is bound to
a receptor
2. Ligand (epinephrine, glucagons, etc.) binds to receptor
3. subunit of G-protein exchanges GTP for GDP and
dissociates from the andsubunits and the receptor
4. adenylyl cyclase binds to GTP-GS, which activates
adenylyl cyclase and increases synthesis of cAMP
a. cAMP from ATP
b. cAMP hydrolyzed to AMP by cAMP
phosphodiesterase (resides in membrane)
c. insulin lowers cAMP levels
d. cAMP is an allosteric activator of protein kinase A
1. serine-threonine protein kinase
5. GS inactivates itself by hydrolyzing GTP to GDP
6. GS rejoins the other subunits and binds to receptor
C. When a C.M. binds to a receptor, the signal it is carrying must be converted into
an intracellular responsesignal transduction
III. Signal Transduction for Intracellular Receptors
A. most intracellular receptors are gene-specific transcription factors
1. bind to DNA and regulate the transcription of various genes
2. transcription = DNARNA
IV. Signal Transduction for Plasma Membrane Receptors
A. mechanisms of signal transduction that follow the binding of a C.M. to the
plasma membrane include:
1. phosphorylation of receptors at tyrosine residues (tyrosine kinase act.)
2. conformational changes in signal transducer proteins
a. proteins with SH2 domains
b. monomeric G-protein RAS and heterotrimeric G-proteins
3. increases in the levels of intracellular second messengers
a. nonprotein molecules
b. cAMP
c. inositol triphosphate (IP3)
d. diacylglycerol (DAG)
B. Signaling requires rapid response and termination of the message
1. achieved by:
a. degradation of the messenger or second messenger
b. automatic G-protein clock
c. deactivation of signal transduction kinases by phosphatases