Term
| What are 4 types of second messenger systems? |
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Definition
1) Hydrophilic Cyclic nucleotides (cAMP, cGMP) located within cells
2) Hydrophilic Calcium located within cell
3) NO Gas (also CO)- diffuse across membranes
4) Hydrophobic DAG/IP3- membrane-associated and then diffuse |
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Term
True: False
Second Messengers are rapidly synthesized and degraded, achieving highly localized actions |
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Definition
True!
Also, synthesis and degradation is regulated by enzymes |
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Term
| Which hormones act through cAMP? |
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Definition
Pituitary- ACTH, LH, TSH, vasopressin (ADH)
Adrenal- E, NE,
Pancreas- Glucagon
1) Epinephrine (adrenaline) and NE/ increases heart rate and triggers glucose release
2) Glucagon in pancreas (glycogen to glucose in liver) (fast response of PKA)
3) ACTH in pituitary- stimulates glucocorticoid production in adrenal glands.
4) Vasopressin- water retention
5) Luteinizing hormone in pituitary- testosterone synth and secretion in males, ovulation in females.
6) Thyroid-stimulating hormone in pituitary- stimulates thyroid gland to secrete thyroxine and triodothyronine. |
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Term
| Why is a mutation in the Adenylyl cyclase enzyme of clinical relevance? |
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Definition
| Plasma membrane enzyme that is critical for making cAMP from ATP (activated by hormone such as adrenaline through binding to cell-surface receptor). |
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Term
| How do Methyl Xanthines such as caffeine exert their effects? |
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Definition
They are cAMP phosphodiesterase inhibitors!
Recall, cAMP is deactivated by cAMP phosphodiesterase, so caffeine prevents this degradation and leads to aberrant cAMP signaling and activation of PKA.
Note- binding of cAMP to regulatory subunits of PKA tetramer leads to release of catalytic subunits which phosphorylate target proteins in a Fast or Slow manner. |
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Term
1) How can CREB mediate gene transcription?
2) How is this signaling cascade deactivated? |
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Definition
1) PKA catalytic subunits enter the nucleus through the NPC and bind CREB, thereby recruiting CREB binding proteins (CBPs) which act as coactivators
CREB/CBP complex binds Cre Response Elements (CREs) in the promotors of genes to alter transcription.
2) PKA phosphorylates phosphodiesterase (PDE), which converse cAMP to 5'-AMP, thereby reducing cAMP levels.
Also, S/T phosphoprotein phosphatases (PPs) remove phosphates from proteins. PPI specifically dephosphorylates proteins phosphorylated by PKA |
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Term
| A patient presents with severe alcoholism and an addiction to smoking. You also notice defects in memory. What might be going on here in relation to dopamine signaling? |
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Definition
CREB is involved in all of these functions, especially ADDICTION
We know PKA mediates effects of dopamine (elevated in smoker's brains), so abnormal PKA signaling is probably altering Dopamine expression through CREB-mediated transcriptional control |
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Term
| A patient presents with severe chest pain. Why might you give them Epinephrine? |
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Definition
This is a simple chain of events.
Epi.....increase in cAMP.....increase in PKA.......MLCK activated
ultimately leading to increased cardiac contractility, increasing blood flow and limiting cell death. |
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Term
| A patient presents with congenital heart defects, broad thumbs and toes, a beak nose and feeding difficulties. You are guessing Rubinstein-Taybi syndrome, but since the case only occurs in 1/125,000 cases, what gene do you investigate to confirm? |
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Definition
Rubinstein-Taybi Syndrome is a CBP mutation.
Remember, CBP is an important transcriptional coactivator for CREB-mediated gene expression. |
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Term
| Why might the phosphodiesterase type IV inhibitor, rolipram be prescribed for Huntington's disease? |
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Definition
| Huntington's is associated with decreased CREB activity. PDEIs like rolipram will prevent the degradation of PKA, thereby increasing CREB phosphorylation. |
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Term
| How do the GC-A, GC-B and GC-C Guanylyl cyclase enzymes differ in their responsivity? |
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Definition
Remember, GCs can be membrane bound or soluble (activated by NO/ critical for vasodilation).
GC-A and GC-B reponse to natriuretic factors such as peptides that induce sodium discharge in the urine
GC-C is activated in response to guanylin (regulating water and electrolyte transport in intestine and kidney) |
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Term
| How is NO synthesized and how does it influence vasodilation? How is it inactivated? |
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Definition
Hydrophobic free radical gas with 1-5 s half-life.
1) Synthesized by NO synthase (activated by Ach binding) from Arginine and requires O2 and NADPH
2) Binds soluble Guanylyl Cyclase enzymes, increasing cGMP
3) iNOS (induced) in macrophages, nNOS in neurons and eNOS in blood vessels are all innactivated by O2 or binding to Hb. |
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Term
| The heart of a patient is having issues "filling." Why might you suspect an Ariginine deficiency? |
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Definition
NO relaxes smooth muscle in arterioles, and when the heart contracts, this relaxing enables the heart to fill.
NO is synthesized from Arginine. |
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Term
| Why is nitroglycerin administered to treat arterial plaques causing Angina, BP in prenatal infants and bacterial infections? |
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Definition
| It produces NO which is a vasodilator and a direct killer of bacteria. |
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Term
| How is PKG activation different from PKA? |
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Definition
PKG is a dimer and PKA is a tetramer
PKG catalytic subunits do not dissociate, while PKA subunits do.
PKG actually phosphorylates PKA! |
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Term
| Might might color-blinded individuals be concerned about mutations in Guanylyl Cyclase? |
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Definition
| cGMP binds directly to cyclic nucleotide gated ion channels in the cones of the retina! |
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Term
| Why is aberrant cAMP signaling associated with deficits in learning and memory? |
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Definition
| cAMP binds and opens ion channels in the prefrontal cortex, which stops information flow into that cell from other inputs in the brain! |
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Term
| How does Viagra work to treat erectile disfunction? |
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Definition
Inhibitor of cGMP phosphodiesterase type 5.
This enzyme usually degrades cGMP, thereby preventing the vasodilatory effects of NO. If it is inhibited, these effects are reversed in the corpus cavernosum.
Note- such inhibitors are also used to treat pulmonary hypertension and coronary heart disease. |
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Term
| What factors does the duration of calcium signals in the cytosol depend on? |
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Definition
1) Time of initiating signal cascade
2) type of ion channel
3) rate of Ca export out of cell
4) rate of binding target proteins
5) rate of dissociation from target proteins.
Recall. low cytoplasmic concentrations are obtains by maximizing export, pumping Ca into ER, sarcoplasmic reticulum and mitochondria for safe keeping, and molecules that bind up free calcium. |
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Term
| Why are drugs such as felodipine used to treat high blood pressure? |
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Definition
| They inhibit voltage-gated calcium channels which regulate muscle contraction in the smooth muscle walls of arterioles. |
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Term
| How does IP3 relate to calcium signaling? |
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Definition
| IP3 releases calcium from ER into the cell cytosol! |
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Term
| Why might a mutation in a ryanodine receptor be clinically significant? |
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Definition
Particularly relevant in the heart, where these mutations can cause primary arrythmogenic disorders.
Remember, RyRs are present in sarcoplasmic reticulum, where they release calcium for muscle contraction. This is why when snake venom inhibits RyRs, it causes paralysis
Also present in ER of non-muscle cells |
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Term
| How are calcium levels kept low within the cell? |
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Definition
1) Plasma Membrane Ca ATPase (PMCA) is a high affinity, slow calcium exporter.
1 ATP per 2 Ca
2) NCX
3) ER pump to take up calcium against concentration gradient
4) low-affinity, high capacity Ca pump in inner mitochondrial membrane that keeps cytosolic levels low after stimulation. |
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Term
| Why might neurons express the exchanger protein NCX? How does NCX differ from PMCA in terms of activity? |
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Definition
Neurons make high use of calcium.
This exchanger takes 3NA in for every Ca out, using the sodium gradient to power itself.
PMCA= high affinity, slow, ATP-dependent
NCX= low affinity, fast, uses Na-gradient |
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Term
| Why is NCX important for nerve cells in response to traumatic brain injury, while PMCA is more important for sensorineural deafness? |
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Definition
NCX is for rapid response!
PMCA is slower and higher affinity (sensorineural deafness is a chronic, long-lasting condition). |
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Term
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Definition
1) Calcium activates calmodulin (CaM) (4 Ca molecules) in plasma membrane or cytosol
2) CaM binds CaM-kinases (N-term catalytic, regulatory, association domains) and inhibits auto inhibition by pseudosubstrate in regulatory domain.
3) CaM-kinases phosphorylate eachtoerh, a)increasing affinity for Ca/CaM, preventing its dissociation and increasing activity time and b) enhancing kinase activity by making an Ca-independent catalytic site
Important in the brain!!!
Note- CaM Kinase activity increases as function of Ca pulse frequency, therefore activating as a pulse frequency decoder. |
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Term
| DAG is a common additive found in bread and ice cream, and it is derived by animals and soybean. How is it produced? |
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Definition
PIP2 in inner half of plasma membrane breaks down to form DAG
1) Receptor-mediated activation of membrane-bound Phospholipase C (PLC) cleaves PIP2 to generate IP3 and DAG
2) IP3 is water soluble and diffuses through cytosol to bind and open IP3-gated ion channels in smooth ER, where Ca is released activating Ryanodine receptors, leading to further Ca release.
3) DAG remains membrane bound, until it is cleaved to produce arachodonic acid, which can act to synthesize lipids. |
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Term
1) How can DAG synthesis bring about cellular changes (PKC activation)?
2) Why is this pathway clinically relevant? |
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Definition
1) IP3 production increases intracellular calcium signaling, which activates (with DAG) PKC to move from the cytosol to the plasma membrane.
2) Graft rejection, cancer and CV disease! Must inhibit.
FK506 and cyclosporin prevent graft rejection by blocking this PKC pathway!
PCK-activation via phorbol esters promotes tumor formation and selective PKC activators induce multidrug resistance in human cancer lines. PCK is also involved in CV disease.
Targeted inhibition is therefore a goal!!!!1 |
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