Mstn Ii - Lecture 26

Front 1

lipophilic hormones, lipid-soluble hormones

Back 1

diffuse across membrane -> interact with intracellular receptors in cytosol or nucleus

eg: steroids, progestrone, estradiol, testosterone, thyroxine, retinoids

Front 2

lipophilic, bind to cell surface receptors

Back 2

e.g prostaglandins

Front 3

hydrophilic, water soluble molecules

Back 3

cannot diffuse across the membrane, bind to cell-surface receptors

e.g. peptide hormones, insulin, growth factors, glucagon, small charged molecules from AAs, epinephrine, histamine

Front 4

G protein coupled recetpors (GPCRs)

Back 4

ligand (epinephrine, glucagon) binds to receptor -> activates a G protein which binds to an enzyme -> catalyzes synthesis of a specific second messenger or the modification of an ion channel.

Front 5

Ligand-gated Ion-channel receptors

Back 5

ligand (acetylcholine) binding -> conformational changes in the receptor -> create a channel for movement of specific ions -> changes in electric potential across the membrane

Front 6

Guanylyl Cyclase Receptors

Back 6

Ligand (atrial naturetic factor, ANF) binding activates the receptor which acts as a monomer. Activated receptor generates cGMP, a second messenger, from GTP.

Front 7

Receptor Tyrosine Kinases, RTKs

Back 7

ligand (hormone or growth factor) binding -> activation of the receptor -> receptor phosphorylates tyrosine residues on itself and of other substrates.

Front 8

Tyrosine Kinase-linked receptors (cytokine-receptor superfamily)

Back 8

ligand (interferons and human growth hormone) binding -> receptor dimerization-> receptor binds to a cytosolic protein tyrosine kinase. The bound Tyr kinase is 'activated' and it tyrosine phoshorylates the receptor.

Front 9

structure of G Protein-Coupled Receptors (GPCRs)

Back 9

- 7 transmembrane domains (all alpha-helices)
- extracellular N-terminus and intracellular C-terminus

- loops b/w alpha helices 5 and 6, and 3 and 4 are important for interaction with the coupled G protein.

Front 10

examples of GPCRs

Back 10

- large numbers of homrones and neurotransmitters
- light-activated receptors in the eye (rhodopsins)
- odorant receptors in the nose

Front 11

Catecholamine receptors

Back 11

- bind charged molecules such as epinephrine (adrenaline) and norepinephrine (noradrenaline)

- side chain containing NH group is important for affinity towards the receptor, and the catechol ring is important in increasing the cAMP level.

Front 12

Epinephrine binds to:

Back 12

- beta-adrenergic receptors (on liver cells/adipose cells/cardiac muscle cells/smooth muscle cells of the intestine)
- alpha-adrenergic receptors (on smooth mucle cells of the blood vessels)

Front 13

Epinephrine bound to the beta-adrenergic receptors on smooth muscle cells of the intestine causes:

Back 13

muscle relaxation

Front 14

Epinephrine bound to the alpha2-adrenergic receptor on smooth muscle cells lining the blood vessels in the intestine, skin, and kidneys causes:

Back 14

constriction of the arteries, cutting off circulation to these peripheral sites.

Front 15

Agonists

Back 15

- chemical analog of epinephrine
- bind to the beta-adrenergic receptor
- beta 2 receptors on the smooth muscle cells lining the bronchial passage -> muscle relaxation

Front 16

Terbutaline

Back 16

-treatment for asthma
- a beta 2 selective agonist, is used to open up the bronchioles in the lungs.

Front 17

Antagonists

Back 17

chemical analogs of epinephrine
- bind to the receptor and cause competitive inhibition of the hormone action by blocking the hormone binding sites on the receptor.

Front 18

Treatment of cardiac arrhythmia and angina

Back 18

beta blockers such as practolol function as beta 1-selective antagonists, slowing heart contractions.

Front 19

Epinephrine bind to beta adrenergic receptors:

Back 19

increase in intracellular level of cAMP

Front 20

helices 3 and 4 of adrenergic receptors:

Back 20

the cytosolic loop joining helices 3 and 4 contributes to G protein binding

Front 21

helix 7 of the adrenergic receptor:

Back 21

determines ligand specificity

Front 22

beta 1 and beta 2 adrenergic receptors bind to:

Back 22

Gs protein (stimulatory G protein) - stimulates the membrane-bound effector enzyme adenylyl cyclase -> rise in intracellular level of cAMP.

Front 23

Adenylyl Cyclase

Back 23

has two catalytic domains facing the cytosol to which ATP molecules can bind.

6 transmembrane domains (alpha helices)

both N and C terminus are intracellular

converts ATP from cytosol to cAMP and pyrophosphate (PPi)

Front 24

Gq protein

Back 24

alpha1 adrenergic receptors are coupled to it.

stimulate phospholipase C (PLC) to generate second messengers, IP3 and DAG

Front 25

Gi protein

Back 25

inhibitory G protein

alpha 2 adrenergic receptors are coupled to it, inhibits adenylyl cyclase.

Front 26

How many subunits does G protein have?

Back 26

3

alpha, beta, gamma

Front 27

active G protein:

inactive G protein:

Back 27

GTP-bound form

GDP-bound form

Front 28

when ligand is not bound to a beta-adrenergic receptor:

Back 28

the alpha subunit of Gs protein (Gsalpha) is bound to GDP and complexed with Gsbeta and Gsgamma subunits.

Front 29

when ligand is bound to a beta-adrenergic receptor:

Back 29

changes the conformation of the receptor, allowing its binding to Gsalpha, and displacing GDP. Receptor bound Gsalpha binds GTP.

Gsalpha.GTP dissociates from the Gsbeta.Gsgamma portion of the trimer, and binds to and activates adenylyl cycclase.

Front 30

GTPase activity of G Protein:

Back 30

cause GTP-bound Gsalpha hydrolyzes GTP to GDP within seconds, resulting int he reassociation of Gsalpha with Gsbeta and Gsgamma, and inactivation of adenylyl cyclase

Front 31

In adipose cells, epinephrine, glucagon, and ACTH recepotrs interact with:

Back 31

and activate Gs proteins, converting Gsalpha.GDP to Gsalpha.GTP.

Gsalpha.GTP binds to and activates adenylyl cyclase leading to an increase in cAMP lvel.

Front 32

Prostaglandin PGE1 and adenosine receptors intereact with:

Back 32

Gi protein, which contains the same beta and gamme subunits but a different alpha subunit (Gialpha).

activation leads to Gialpha.GTP complex formation which inhibits adenylyl cyclase.

Front 33

Gs

stimulate:

inhibit:

Back 33

stimulate: Phospholipase C -> cAMP

stimulate: Ca2+ channel -> Ca2+

inhibit: Na+ channel -> change in membrane

Front 34

Gi

stimulate:

inhibit:

Back 34

inhibit: adenylyl cyclase -> cAMP

stimulate: K+ channel -> Change in membrane

inhibit: Ca2+ channel -> Ca2+

Front 35

Gq

stimulate:

Back 35

stimulate: phospholipase C -> IP3, DAG

Front 36

Go

stimulate:

inhibit:

Back 36

stimulate: phospholipase C -> IP3, DAG

inhibit: Ca2+ channel -> Ca2+

Front 37

Gt

stimulate:

Back 37

stimulate: cGMP phosphodiesterase -> CGMP

Front 38

Gbetagamma

stimulate:

inhibit:

Back 38

stimulate: phospholipase C -> IP3, DAGr

inhibit: adenylyl cyclase -> cAMP

Front 39

effect on beta adrenergic receptors in the presence of Gsalpha.GTP:

Back 39

decrease in the hormone affinity

Front 40

inactivation of adenylyl cyclase:

Back 40

intrinsic GTPase activity of the alpha subunit aloows it to be relreased from adenylyl cyclase, thereby inactivating the enzyme and cAMP production.

Front 41

cyclic nucleotide phosphodiesterase

Back 41

hydrolyzes cAMP -> 5' AMP (needs the presence of cytosolic Ca2+) and terminates the effect of the hormones.

caffeine, theophylline inhibits it

Front 42

cholera toxin

structure and symptoms

Back 42

-hexameric protein
- 1 alpha subunit and 5 beta subunits
- produced by the cholera causing bacterium Vibrio cholerase
- symptoms: diarrhea due to water flow from the blood through the intestinal epithelium into the lumen of the intestine

Front 43

cholera toxin

how it works:

Back 43

- alpha subunit of the toxin enters the cytosol and catalyze ADP-ribosylation
- add ADP ribose (from NAD+) to arginine residues and modifies Gsalpha proteins. Removing their GTPase activity. -> continuously activated adenylyl cyclase, and >100 fold increase in the cAMP. -> activates Cl- channel (CFTR channels)

Front 44

mutations at Arg201 of Gsalpha

Back 44

lack of GTPase activity and have been found in a subset of growth hormone producing pituitary tumors and in thyroid adenomas.

Front 45

Pertussis Toxin

Back 45

secreted by Bordetella pertussis
- causes whooping cough.
- S1 subunit of this toxin causes ADP-ribosylation of the alpha subunit of Gi. -> prevents release of GDP, leaving Gi in the DP-bound state (inactive).
- once inactivated, adenylyl cyclase activity proceeds and the cell produces increased amounts of cAMP.

Front 46

Excitatory Chemical Synapses

Back 46

- neurotransmitter bind to an excitatory receptor on the postsynaptic cell
- open up a channel that admits Na+ and/or K+
- membrane depolarization and generation of an action potential in the post-synaptic cell

Front 47

Inhibitory Chemical Synapses

Back 47

- neurotransmitter bind to an inhibitory receptor
- open K+ or Cl- channels
- membrane hyperpolarization
- inhibition of generation of an action potential in the post-synaptic cell

Front 48

Excitatory Receptors

Back 48

- acetylcholine (nicotinic receptor) -> Na+/K+
- Glutamate (NMDA class receptors) -> Na+/K+ and Ca2+
- Glutamate (non-NMDA class receptors) -> Na+/K+
- Serotonin (5HT3 class receptors) -> Na+/K+

Front 49

Inhibitory Receptors

Back 49

- gamma-Aminobutyric acid, GABA (A-class receptors) -> Cl-
- Glycine -> Cl-

Front 50

2 Categories of Acetylcholine receptors

Back 50

1) nicotinic acetylcholine receptors = ligant-gated ion-channel receptors that are ligand-gated channels for Na+ and K+ ions

2) MMuscarinic acetylcholine receptors that are couples to G proteins

Front 51

Neurotransmitter Receptors

Back 51

- ligand-gated ion channels
- 5 subunits, each contains a transmembrane alpha helix (M2) that lines the channel
- binding of a neurotransmitter to the receptor causes conformational change leading to opening of the channel
- Aspartate and glutamate side chains at both ends of the M2 helix form two rings of negative charges that facilitae attraction of cations to the channel.

Front 52

Cardiac Muscarinic Acetylcholine Receptors Activate:

Back 52

a G protein that opens up K+ channels

Front 53

Cardiac Muscarinic acetylcholine receptors

Back 53

- G protein coupled neurotransmitter receptors containing 7 transmembrane alpha helices and induce signaling pathways similar to those in non-neuronal cells.

Front 54

Binding of acetyccholine to muscarinic acetylcholine receptors in cardiac muscle cells generates:

Back 54

- a low inhibitory response
- one of the principal means of slowing down the rate of heart muscle contraction

Front 55

activation of the cardiac muscarinic acetylcholine receptor (G-protein coupled receptor)

Back 55

- activated a trimeric G protein
- released Gbetagamma subunit binds to and opens a K+ channel -> hyperpolarization of the plasma membrane -> decreases the rate of heart muscle contraction

Front 56

termination of muscarinic acetylcholine receptors:

Back 56

Galpha bound GTP is hydrolyzed to GDP and Galpha.GDP joins with Gbetagamma.