Chemical Signaling
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- steroid hormone receptors -- describe the pertinent features of the C terminal
-
relatively conservative
involved with HSP 90
steroid binding
dimerization - steroid hormone receptors -- describe the pertinent features of the N terminal
-
least conserved
required for the maximum gene transcription activity - steroid hormone receptors -- describe the pertinent features of the central domain
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cystein rich
folded into two zinc finger motifs
highly conserved - down regulation
- receptor disappears from the cell surface
- cell surface receptors: what are the three main groups (classified according to output)
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(1) enzyme-linked (intrinsic or associated tyrosine kinase activity)
(2) those linked to heterotrimeric G proteins
(3) those that form ion channels - what are four examples of PTKs (receptors with intrinsic tyrosine kinase activity)?
- Insulin, IGF-1, EGF, and PDGF receptors
- give the general structure of the receptors with intrinsic tyrosine kinase activity
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N-terminal extracellular domain (hormone binding)
single transmembrane helix
C-terminal cytoplasmic domain (tyrosine kinase activity and several phophorylation sites) - what are the three AAs that can be phosphorylated?
- threonine, tyrosine, serine
-
receptors with intrinsic tyrosine kinase activity
Group I
- characteristics
- e.g. -
no subunits
EGF -
receptors with intrinsic tyrosine kinase activity
Group II
- characteristics
- e.g. -
two subunits:
N-terminal alpha
C-terminal beta
two form tetramer
e.g. Insulin and IGF-1 -
receptors with intrinsic tyrosine kinase activity
Group III
- characteristics
- e.g. -
no subunits
PDGF - describe the extracellular region of the PDGF receptor?
- five immunoglobin-like domains (N-terminal)
-
receptors having associated tyrosine kinase activity
e.g.
structure -
receptors for prolactin, growth hormone, erythropoietin, interferons (IFNs) and interleukins 2, 7, 10, 13, and 15
extracellular domain with four cysteine moieties for disulfide bonding and a potential site for glycosylation - Janus kinases
- receptors having associated tyrosine kinase activity often work through these, which phosphorylate various target proteins when the ligands bind its receptor
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receptors linked to heterotrimeric G proteins:
Beta 1 and beta 2-adrenergic receptors
- fxn - activate adenylyl cyclase
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receptors linked to heterotrimeric G proteins:
alpha 2-adrenergic receptors
- fxn - inihibit adenylyl cyclase
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receptors linked to heterotrimeric G proteins:
alpha 1-adrenergic receptors
- fxn - activates phospholipase C
- what is an example of a receptor that forms a sodium channel?
- nicotine acetylcholine receptor
- what are two examples of receptors that form a chloride channel?
- gamma-amino butyric acid (GABA) and glycine receptors
- describe the structure of the nicotine acetylcholine receptor
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five subunits (alpha, beta, gamma, sigma, epsilon)
each has an extracellular domain, four or five transmembrane helices, and a large cytoplasmic domain - what are the six major signal transduction pathways?
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1. cAMP pathway
2. Calcium-Phospholipid pathway
3. cGMP pathway
4. G-Ras protein-linked pathway
5. JAK-STAT pathway
6. Cytoplasmic serine phosphorylation and / or proteolysis pathways -
stimulatory G protein (Gs)
- how does it help make cAMP? -
ligand binds to receptor, which is linked to a heterotrimer G-protein
causes conformational change that allows GTP to replace GDP on alpha subunit
alpha subunit disengages and attaches to adenyl cyclase, which activates the enzyme to produce cAMP from ATP - what effect do GRFs have on stimulatory G proteins?
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GRFs = guanosine nucleotide releasing factors
these help GDP dissociate from alpha subunit, so GTP can rapidly bind - what effect do GAPs have on stimulatory G proteins?
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GAPs = GTPase activating proteins
facilitate the hydrolysis of GTP to GDP by intrinsic ATPase of the alpha subunit - once cAMP is formed, what is the next step?
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cAMP binds to the two regulatory (R2) subunits of PKA
R2 dissociates from C2 (catalytic subunits)
C2 phosphorylate various proteins and transfer the terminal phosphate group from ATP to specific serine or threonin residues, causing a cascade of cellular events - once the cAMP cascade has been activated, how does the cell return to normal?
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dephosphorylation of phosphorylated serines and threonine by phosphatases
metabolizing cAMP to inactive 5' AMP by one of more cAMP phosphodiesterases (PDE) - Are cAMP levels maintained by changing the phosphodiesterase activity?
- no, levels are maintained by activating or inhibiting adenylyl cyclase
- how does the cholera toxin work?
- catalyzes the transfer of ADP-ribose from NAD+ to the alpha subunit of Gs, locking GTP into an unhydrolyzable state -- too much cAMP is made, leads to Na+ and water efflux into the gut, diarhhea
- how does inhibitory G protein work?
- same as stimulatory G protein except the GTP-bound form of the alpha subunit inhibits adenyl cyclase
- how does the pertussis toxin (whooping cough) work?
- ADP-ribosylation of inhibitory alpha G protein, meaning that it can't inhibit adenylyl cyclase
- name three ways that cytosolic Ca2+ can be kept low
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(1) Ca2+-ATPase pump to ECF
(2) Na+/Ca2+ exchanger (uses Na+ gradient)
(3) Ca2+-ATPase pump to intracellular compartment - Name the two ways cytosolic Ca2+ levels can be raised from 10-7 to 5x10-6
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voltage-gated Ca2+ channels in electrically excitable tissues
receptor-activated Ca2+ channels (calcium-phospholipid pathway) - 4 good things to know about calmodulin
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(1) found in plants and animals
(2) highly conserved)
(3) multifxnal
(4) single peptide - does calmodulin have enzymatic activity?
- no direct enzymatic activity, but it activates other proteins by binding to them
- what do ANPs do?
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ANP = atrial natriuretic peptide
secreted by muscle cells in the atrium of the heart when BP rises, increase Na+ and water excretion and enhance relaxation of smooth muscle cells of the blood vessels, thus lowering BP - is there G-protein involvement in the ANP pathway?
- no, it is a direct linkage between ligand binding and activation of guanylyl cyclase
- show the ANP pathway
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ANP binds to extracellular domain
up guanylyl cyclase
up cGMP
up G-kinase
up phosphorylation of serines and threonines
up biological responses - how are Na+ channels regulated in retinal rod cells?
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in absence of light Na+ channels are open
when light hits rod cells, rhodopson activates Gt (G protein transducin)
the alpa subunit dissociates and activates cyclic GMP phosphodiesterase
this hydrolyses channel bound cGMP, which closes the Na+ channels - chart the Ras pathway
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growth factors such as EGF and PDGF, insulin, and IGF-1
- binding of ligand to receptor results on dimerization and autophosphorylation
- phosphotyrosine residues cause receptors to bind to GRB-2
- through SOS activates G-Ras by GTP-GDP exchange
- G-Ras acts on protein kinases such as MAPKs
- gene expression