Receptors And Cell Signaling Flashcards
The Leptin gene is _____________ and is the “satiety signal”
Its counterpart ___________ also acts on the hypothalamus and is named the “hunger hormone”
Recessive
Ghrelin
___________ alter the activity of different components downstream a signaling event and generate secondary messengers
Effectors
____________ signals are transported via blood (hormones) and are ______-lasting.
The ligand can be ______________ or stored in a vesicle
Endocrine
Long
Hydrophobic
____________ signals diffuse to neighboring target cells of a different type. These are short lived, local signal molecules
Paracrine
What is the main biologic example of paracrine signaling?
Neurotransmission
___________ signals occur when secreting cells express surface receptors for that signal
Autocrine
Growth factors in cancer cells utilize what type of signaling?
Autocrine
Epinephrine released by the adrenal medulla acts on heart muscle - this is an example of what type of signaling?
Endocrine
____________ refers to when signal binds to the signaling cell which then binds to receptor on the target cell. This occurs with immune cells.
Direct/Juxtacrine
_________ signals freely diffuse accross PM’s
____________ signals undergo gradient-dependent diffusion
___________ signals require an active transport mechanism
_______ signals utilize ion channels
Hydrophobic
Small, uncharged, polar
Large, uncharged, polar
Ions
__________ signals are lipid-soluble and diffuse freely through membranes and interact with receptors in the cytosol or nucleus
Lipophilic
[note that these must be bound to carrier proteins to be transported through the blood]
What are the 2 different types of lipophilic receptors?
Cytoplasmic - form complex with HSP and dissociate upon signal binding, translocating it to the nucleus where it binds a DNA sequence and alters rate of transcription
Nuclear - present in the nucleus bound to DNA. Alters transcription of certain genes after signal binding
Describe hydrophilic signals
Water-soluble, cannot diffuse through membrane
Bind to surface receptors and trigger downstream events
Generally small and derived from AA’s, have shorter half lives
What are 2 types of hydrophilic receptors?
GPCRs - mediated by G proteins, effector proteins, second messengers, 7-alpha helices
RTKs - mediated by monomeric G proteins and protein kinases, 1-alpha helix
What type of receptor is considered to be in the enzyme-coupled receptor class?
RTKs
Epinephrine stimulates glycogen metabolism by promoting __________ secretion
If glycogen stores are depleted, ________ stimulates gluconeogenesis by inducing enzymatic transcription
Under fed conditions, ________ promotes glycogenesis and glycolysis, and inhibits synthesis of gluconeogenesis enzymes
Glucagon
Cortisol
Insulin
Oral contraceptives have long half-lives and are taken daily. What type of signal molecules do they contain?
Lipophilic
Epinephrine has a short half-life and is administered at the time it is needed. What type of signal does it contain?
Hydrophilic
Graves disease is an autoimmune disorder in which thyroid stimulating immunoglobulin binds to and overstimulates TSH receptors, causing hyperthyroidism, including:
Decreased _________
Increased ______ and _______
TSH
T3 and T4
What are the clinical manifestations and treatment options for Grave’s disease?
CM - weight loss, tachycardia, insomnia, pretibial myxedema, exophtalmos, goiter
TX - surgical resection of thyroid, radioactive iodine
Describe the structural motif of GPCRs
ECD binds to signal
TMD composed of 7 alpha helices
ICD interacts with G proteins
GPCRs are arranged in a _______ pattern within the membrane, contain an extracellular ________ bond
They contain conserved _______ and ______ residues as well as a C-terminus tethered to the membrane
Circular; disulfide
DRY; WP
GPCRs are active in adrenergic pathways and are targets of ______________, especialle NE and Epi
Catecholamines
GPCRs are canonical in structure but diverse in function. What types of ligands can they recognize?
Light (rhodopsin), hormones, peptides, proteins, NT’s
The same signaling molecule may produce different physiological responses in the same targets of different cells:
Binding of epi to beta-adrenergic receptors causes _______ of bronchial and intestinal smooth muscle
Binding of epi to beta-adrenergic receptors causes _______ in heart muscle
Relaxation
Contraction
[binding produces same second messenger - cAMP - in both, but downstream pathways diverge resulting in diff responses]
Trimeric G proteins have 3 subunits: ______, _____, and ______
They also have ________activity
Alpha, beta, gamma
GTPase
trimeric G proteins act as molecular on-off switch
They are on when the ______ subunit is bound to GTP
They are inactive when bound to _______
Alpha
GDP
_______ are proteins that activate G proteins by promoting exchange of GDP for GTP
GEFs (guanine exchange factors)
______ proteins speed up the inactivation of G proteins by promoting GTPase activity
GAP
With GPCRs, once the GTP-bound, alpha-subunit interacts with an effector protein to either activate or inactivate it, it can catalyze reactions that produce second messengers.
What is the typical effector protein in most GPCR-related biologic processes?
Adenylyl cyclase
True or false: GTP-bound means that the G protein is inactivated because the GTP must be hydrolyzed in order to provide the energy needed for that process
False, GTP-bound means that the G protein is activated
Which subunit of a trimeric G protein interacts with the effector molecule?
Alpha
Adenylyl cyclase generates _______ from ATP, which activates _____, which directly regulates many pathways via phosphorylation
cAMP
PKA
What are 4 methods of PKA regulation?
- Phosphate group can form part of structure that other proteins recognize
- Activation/inactivation of enzymatic target protein
- Alteration of IC localization of target proteins
- Alterations in abundance of target proteins
When a signal molecule binds a GPCR, activating internal G protein Gi, what is the next step?
Inhibition of AC
Gt activation by light _______ cGMP phosphodiesterase, which is an important process for ____________
Activates
Vision
_______ cleaves PIP2 into DAG and IP3.
______ then translocates to the ER and opens ligand-gated Ca channels
Increased calcium concentration causes translocation of _____ to plasma membrane where it is activated by DAG so it can phosphorylate _______/_______ of target proteins
Calcium also binds to __________, which activates other downstream targets
PLC
IP3
PKC; Ser/Thr
Calmodulin
[moral of the story: Gq activation by PLC activates PKC through secondary process]
Certain enzymes hydrolyze cyclic nucleotides to regulate cellular levels. What enzyme hydrolyzes cAMP to AMP?
cAMP phosphodiesterase
Certain enzymes hydrolyze cyclic nucleotides to regulate cellular levels. What enzyme hydrolyzes cGMP to 5’GMP?
cGMP phosphodiesterase
Inhibitors of cGMP PDE increase concentration of cellular cGMP, leading to what physiological effect?
Smooth muscle relaxation and vasodilation (viagra, levitra, cialis)
What effect does caffeine have on cAMP PDE?
Inhibits it, thus increasing heart rate
Nitric oxide is produced in epithelial cells and is responsible for relaxation of smooth muscles. It diffuses into neighboring muscle and activates _______ ________, leading to the production of cGMP.
What is the desired physiological effect of taking nitrates and what is a possible drug interaction?
Guanylate cyclase
Taken to lower blood pressure. These patients should not take drugs that inhibit cGMP PDE (like viagra) which could lead to extreme vasodilation and drops in BP
What effect do beta agonists like albuterol and epinephrine have on conditions like asthma?
They are beta agonists. Albuterol is hydrophilic and binds to/activates beta-adrenergic receptors
They relax bronchial smooth muscle and stimulate heart muscle contraction
What effect do antihistimines have on GPCRs?
Inhibitory
Histamines, the allergy causing signal molecules derived from _________, bind to the 4 ________ residues in GPCRs
Histidine; histidine
Cholera is usually contracted due to the consumption of water contaminated with the cholera toxin. This causes ribosylation of ________ residues and ________ GTPase activity.
Arg; decreases
So Gsa remains active and overstimulated AC produces too much cAMP –> intestinal cells open Cl channels –> loss of electrolytes and water –> diarrhea
What effect does the pertussis toxin have on G proteins?
ADP ribosylation of Cys on Gia prevents activation and dissociation of a-subunit from G protein complex
So less inhibition of AC, and overproduction of cAMP leads to fluid loss and excess mucous in airway epithelial cells
___________ refers to the ability to turn off or “ignore” a signal
Desensitization
What are 4 possible mechanisms for signal desensitization?
- Hormone levels drop (decreased AC activity, decreased cAMP, decreased PKA activity)
- Removal of signal molecule (PDE removes cAMP/cGMP)
- Receptor sequestration
- Receptor destruction
GRKs ____________ GPCRs, then ___________ binds to the 3rd intracellular loop, preventing Ga from interacting with third loop. The result is that Ga-GDP does not get converted to Ga-GTP
Phosphorylate
Arrestin
Enzyme-coupled reactions occur via RTKs. First, a signal binds to the ECD and induces a conformational change that causes dimerization of the receptor. Specific tyrosine residue is phosphorylized (autophosphorylation). What is the next step?
Phosphotyrosine is recognized and bound by adapter and docking proteins (SH2 domain of Grb2), leading to downstream signaling pathways that are RAS dependent or independent
What would be the result of a mutation or other allosteric effecter causing dimerization of an RTK?
The RTK will remain active
________ domains are found on adaptor proteins that recognize and bind to motifs on the receptors that contain phosphorylated Tyr
Recognition
Examples: SH2 or PTB
What is the difference between activated Ras and inactivated Ras?
Ras-GTP = active
Ras-GDP = inactive
[regulated by MAPkinase pathway]
What would happen if Ras were inhibited by an intracellular injection of Ras-inactivating antibodies?
Cell may no longer respond to some of the EC signals
What would happen if Ras were permanently switched on?
Cell would begin proliferating uncontrollably –> cancer
Given its ability to cause uncontrolled cell division if mutated, what type of gene is Ras?
Proto-oncogene
Insulin signaling occurs via RTK with intermediate scaffold including _______, which binds either Grb2 (Ras dependent) or ________ (Ras independent)
IRS-1
PI3 kinase
What is the result of the Ras-dependent insulin signaling pathway?
Grb-2 = Ras dependent scaffold
Alters gene transcription –> increased transcription of glucokinase
What is the result of the Ras-independent insulin signaling pathway?
PI3 kinase = Ras independent scaffold
Alters protein and enzyme activity –> increased GLUT4 movement to plasma membrane; activation of glycogen synthase
What specific mutation occurs with Ras to turn it from a proto-oncogene to an oncogene?
Mutation decreases GTPase activity and locks Ras in the active, GTP-bound state
Neurofibromatosis is related to Ras, but Ras is not the issue with this type of cancer. What is the mutation?
NF-1 gene, which encodes a GAP for Ras, so RAS is uncontrollably activated in pathways for nerve tissue growth
_______ are the target of pharmacologic inhibitors in certain types of cancer. The breast cancer drug herceptin targets HER2, which belongs to this receptor family.
RTKs
Insulin resistance leads to type II diabetes. One critical aspect is a loss of insulin stimulation of glucose uptake by GLUT4 transporters in adipose and skeletal tissue.
Studies point to reduced activation of ____ by insulin in obese subjects. A source of impairment is probably IRS 1 and 2.
PKB
What is one of the most direct routes for affecting transcription in terms of signaling?
JAK-STAT receptors - transmit info from EC chemical signals to the nucleus resulting in DNA transcription and gene expression
These act as cytokine receptors
