Cell Signaling II Flashcards
Which neurotransmitter is in control of CNS in a person sound asleep?
GABA
What does glutamate do?
Excitatory - opens Na, Ca channels, upregulated in CNS
What are the four main second messengers?
cAMP/cGMP, Ca2+, Inositol triphosphate (ITP), Diacyl glycerol (DAG)
What is the major inhibitory neurotransmitter in the CNS?
GABA
Describe the Gs pathway of protein kinase A (PKA).
1) Epinephrine binds to β2 receptor.
2) Dissociation of Gαs from Gβ and activation of Gαs with GTP - ENZYMATIC
3) Gαs-GTP binds to adenylyl cyclase
4) Adenylyl cyclase makes cAMP – ENZYMATIC
5) cAMP binds and activates PKA
6) PKA adds phosphate to target proteins - ENZYMATIC
What is the general name for enzymes that phosphorylate? For enzymes that dephosphorylate?
Protein kinase
Protein phosphatase
What amino acids to kinases target for phosphorylation?
Serine, Threonine, Tyrosine (Have OH groups)
β 2 agonists like albuterol are bronchodilators. Albuterol binds to β 2 receptors on the smooth muscle in the lungs and results in dilation of airway.
Is formation of cAMP from ATP in the signaling pathway enzymatic (involves signal amplification) or stoichiometric (no signal amplification)?
Enzymatic
Describe the GPCR-dependent mechanism of activation of Protein Kinase C (PKC).
1) Signal binds GPCR
2) GDP on GPCR replaced with GTP, activating GPCR
3) GTP-bound subunit (Gq) activates Phospholipase C
4) Phospholipase C activates IP3 and DAG
5) IP3 binds Ca2+ channel on inside of cell
6) Ca2+ enters cell from endoplasmic reticulum
7) Ca2+ and DAG bind PKC and activate it
Describe the three subunits of a G protein in a resting, inactive, and activated state.
Resting State - α subunit bound to β γ subunits
Inactive State - GDP-bound G protein with all subunits bound
Activated State - GTP-bound α subunit and dissociated β γ subunit (also activated)
How is heart rate regulated?
Signaling through GPCRs that target sinoatrial (SA) node, the pacemaker of the heart
What is the signaling pathway to decrease heart rate?
1) Parasympathetic nervous system releases Ach
2) ACh binds M2 receptors and GαI
3) Gβγ subunit opens K+ channels
4) GαI decreases cAMP levels
5) Ca2+ channels close
6) Heart rate decreases
What is the signaling pathway to increase heart rate?
1) Sympathetic nervous system releases epinephrine or norepinephrine
2) Epi/Norepi binds β1 receptors and GαS
3) Gβγ subunit increases cAMP levels
4) PKA opens Ca2+ channels
5) K+ channels close
6) Heart rate/contractility increases
Describe allosteric control of adenylate cyclase (AC) and its function.
Binding of Gαs increases adenylate cyclase levels.
Binding of GαI decreases adenylate cyclase levels.
AC converts ATP to cAMP
Where is smooth muscle in our body?
GI tract: bladder, uterus, penis
Also around blood vessels, air way, glands
Explain G protein-coupled signaling in smooth muscle contraction.
Epinephrine binds α1 receptors –> activates Gq –> increases PLC –> increases IP3 –> increases Ca2+ –> CaM kinase increases MLCK activity –> increases myosin-P –> blood vessels and smooth muscle constrict
Epinephrine binds β2 receptors –> activates Gs –> increases AC –> increases cAMP –> increases PKA –> increases MLCP –> decreases myosin-P –> blood vessels and smooth muscle dilate/relax
Albuterol (modified epinephrine) is a drug commonly used to treat asthma. What would be the correct signaling cascade that corresponds to albuterol relaxing bronchial smooth muscle resulting in dilation of airway?
Increase GαS –> increase AC –> increase cAMP –> increase PKA –> increase MLCP –> decrease myosin-P
Describe how signaling by nitric oxide leads to dilation of coronary arteries, increasing blood flow to heart muscle.
Nitroglycerin –> Nitric oxide increases –> guanylyl cyclase increases –> cGMP increases –> PKG increases –> MLC phosphatase increases –> myosin-P decreases –> relaxation of heart muscle
T or F. It’s safe for men on nitrates to take viagra.
False! This could lead to unsafe drop in blood pressure.
Describe mechanisms of Viagra in terms of going from a flaccid penis to an erect penis.
Flaccid penis is result of low cGMP and low venous BP due to open veins.
Erect penis is result of high cGMP levels, leading to veins closing and arteries dilating, creatig high arterial BP.
Normally nitric oxide causes high levels of cGMP. Phosphodiesterase converts cGMP to GMP to restore balance. Viagra inhibits PDE5, causing more/longer erections.
How is signaling terminated for epinephrine?
1) Methylation by enzyme COMT (in liver and blood)
2) Oxidaiton by enzyme MAO (monoamine oxidase)
How is signaling terminated on G proteins?
They have intrinsic GTPase activity and thus inactivate themselves.
GAP (GTPase activating protein) accelerates hydrolysis/inactivation.
How is signaling terminated by cAMP and cGMP?
Phosphodiesterases cleave them to AMP, GMP
How is IP3-dependent Ca2+ signaling terminated?
1) IP3 is dephosphorylated to IP2 (inactive form) by spcific phosphatase.
2) IP3 phosphorylated to form IP4 (inactive form)
3) Ca2+ pumped out of the cytosol ATP-dependent pumps
How is cytoplasmic calcium removed from cytoplasm? (5 ways)
1) By Na/Ca exchanger
2) Pumped out of cells by Ca pump
3) Pumped into sarcoplasmic reticulum by Ca pump
4) Binding to cytoplasmic Ca binding proteins
5) Sequester Ca in mitochondria
What happens to all of the phosphorylated proteins in the cell?
Phosphatases remove phosphates from the proteins constantly - they rule the cells and establish the resting state when kinases are inactive.
Under pathological conditions, will there be a higher or lower level of phosphatase enzymes in blood?
Higher
How is autonomic control of blood supply regulated with epinephrine? How is blood flow changed during emergencies (fight or flight)
By the ratio of α1 and β2 receptors on smooth muscle:
α1, Gq, Ca2+ –> vasoconstriction
β2, Gs, cAMP –> vasodilation
Flow increases to heart, lungs, skeletal muscle
Flow stays the same for the brain
Flow decreases to GI, genitals, skin
How does effect of cAMP change in different cell types?
cAMP increases contraction of cardiac muscle, but relaxes smooth muscle
What is the heart’s intrinsic heart rate when beating on its own without influence out outside signaling?
100 BPM
