What Are Types of Mutations That Would Cause This
Content
What are types of mutations that would cause this? (VERY IMPORTANT TO
UNDERSTAND!) Receptor that is “on” even though there is no ligand
(autoactivation), which results in it continually active as a GEF for Gαs. Making Gαs
so that it canʼt hydrolyze GTP. Stuck in GTP bound form. Pseudohypoparathyroidism
Type 1A Resistant to parathyroid hormone and thyroid stimulating hormone *This
means that hormones have no effect on the receptor that regulates Calcium and
Phosphate metabolism. Leads to decrease in Calcium in the serum, increase in
phosphate PTH and TSH linked to GPCR Disease What type of mutations would
result in this? *Receptor is broken—this is more common; is more specific.
*Inactivation of Gαs
How to limit/turn off receptor signaling cascade? (Know this because these are all
potential targets for test questions regarding signal cascade alteration) 1.
Decreasing the affinity of the receptor for the ligand a. Affinity of receptor changes
for ligand when Gαs-GDP binds and limits the number of Gαs that are activated. b.
This naturally occurs when Gαs-GDP is replaced with GTP. This limits the number of
Gαs that are activated. Also when GTP is bound to Gαs, the probability of the ligand
falling off of the receptor is higher. 2. Intrinsic GTPase activity limits duration of
cAMP production a. Effector acts as GAP for Gαs: Hydrolysis rate is increased when
Gαs binds to Adenylate Cyclase. Hydrolysis is how AC is turned off. b. When Gαs is
bound to GTP before binding AC, the hydrolysis rate is relatively low because it
needs time to bind to AC before it hydrolyses. However, once it has bound, then the
hydrolysis rate is automatically increased. c. AC acts as a GAP for Gαs 3. cAMP
Phosphodiesterase degrades cAMP to 5ʼ-AMP a. This leads to decreased cAMP levels
b. This is the target of caffeine, theophylline (tea), theobromide (chocolate). 4.
Feedback repression a. PKA can phosphorylate receptors (GPCRs). This decreases
the ability to activate Gαs (decreases GEF activity). i. This is an issue because PKA is
not specific for what receptor it phosphorylates. So when PKA is active, it
phosphorylates all receptors. It down-regulates ALL Gαs regulated GPCRs. This
phenomenon is called heterologous desensitization (hits multiple different types of
receptors). 1. Chronic treatment with a ligand for one Gαs coupled receptor can
decrease the efficiency of all Gαs coupled receptors 5. Homologous Desensitization
a. EX. Beta-adrenergic receptor i. It can be Phosphorylated by BARK However, the
same temperature sensitive mutation A336S results in the Gαs protein being
unstable at normal temperature (37degrees), leading to denaturation of protein.
This means that PTH and TSH canʼt activate the receptor; therefore there is no Gαs
activity at all. This leads to pseudo hypoharathyroidism (high PTH) of 10 ii. BARK—Badrenergic Receptor Kinase iii. BARK only phosphorylates receptors that is bound to
ligand
KNOW THIS: One useful tool of studying this is to use antibodies. The antibody that
recognizes the ligand binding domains can bring the monomeric receptors together
in the extracellular domain. Can make an antibody against the receptor of interest
in order to study downstream signaling.
KNOW THIS If the mutation is not part of the checkpoint, then you donʼt get any
division because the checkpoint is in place. However, if the damage ends up being
in the checkpoint detection, then it will just progress through the cell cycle even
though there is damage present.
UNDERSTAND!) Receptor that is “on” even though there is no ligand
(autoactivation), which results in it continually active as a GEF for Gαs. Making Gαs
so that it canʼt hydrolyze GTP. Stuck in GTP bound form. Pseudohypoparathyroidism
Type 1A Resistant to parathyroid hormone and thyroid stimulating hormone *This
means that hormones have no effect on the receptor that regulates Calcium and
Phosphate metabolism. Leads to decrease in Calcium in the serum, increase in
phosphate PTH and TSH linked to GPCR Disease What type of mutations would
result in this? *Receptor is broken—this is more common; is more specific.
*Inactivation of Gαs
How to limit/turn off receptor signaling cascade? (Know this because these are all
potential targets for test questions regarding signal cascade alteration) 1.
Decreasing the affinity of the receptor for the ligand a. Affinity of receptor changes
for ligand when Gαs-GDP binds and limits the number of Gαs that are activated. b.
This naturally occurs when Gαs-GDP is replaced with GTP. This limits the number of
Gαs that are activated. Also when GTP is bound to Gαs, the probability of the ligand
falling off of the receptor is higher. 2. Intrinsic GTPase activity limits duration of
cAMP production a. Effector acts as GAP for Gαs: Hydrolysis rate is increased when
Gαs binds to Adenylate Cyclase. Hydrolysis is how AC is turned off. b. When Gαs is
bound to GTP before binding AC, the hydrolysis rate is relatively low because it
needs time to bind to AC before it hydrolyses. However, once it has bound, then the
hydrolysis rate is automatically increased. c. AC acts as a GAP for Gαs 3. cAMP
Phosphodiesterase degrades cAMP to 5ʼ-AMP a. This leads to decreased cAMP levels
b. This is the target of caffeine, theophylline (tea), theobromide (chocolate). 4.
Feedback repression a. PKA can phosphorylate receptors (GPCRs). This decreases
the ability to activate Gαs (decreases GEF activity). i. This is an issue because PKA is
not specific for what receptor it phosphorylates. So when PKA is active, it
phosphorylates all receptors. It down-regulates ALL Gαs regulated GPCRs. This
phenomenon is called heterologous desensitization (hits multiple different types of
receptors). 1. Chronic treatment with a ligand for one Gαs coupled receptor can
decrease the efficiency of all Gαs coupled receptors 5. Homologous Desensitization
a. EX. Beta-adrenergic receptor i. It can be Phosphorylated by BARK However, the
same temperature sensitive mutation A336S results in the Gαs protein being
unstable at normal temperature (37degrees), leading to denaturation of protein.
This means that PTH and TSH canʼt activate the receptor; therefore there is no Gαs
activity at all. This leads to pseudo hypoharathyroidism (high PTH) of 10 ii. BARK—Badrenergic Receptor Kinase iii. BARK only phosphorylates receptors that is bound to
ligand
KNOW THIS: One useful tool of studying this is to use antibodies. The antibody that
recognizes the ligand binding domains can bring the monomeric receptors together
in the extracellular domain. Can make an antibody against the receptor of interest
in order to study downstream signaling.
KNOW THIS If the mutation is not part of the checkpoint, then you donʼt get any
division because the checkpoint is in place. However, if the damage ends up being
in the checkpoint detection, then it will just progress through the cell cycle even
though there is damage present.
