Lecture 21

Question 1

introduction to receptor guanyl cyclases

Answer 1

• single pass proteins, dimerize, autophosphorylate
• receptor guanylyl cyclases - quintessental example: natriuretic factor
• receptors function as enzymes (analogous to RTKs) -> convert GTP to cGMP
• soluble, NO-activated guanylyl cyclases, contain heme, also convert GTP to cGMP
• cGMP leads to protein kinase G
• atrial natriuretic factor (ANF) and endotoxin use guanyl cyclase receptors

pg 504

Question 2

acetylcholine induced vasodilation

Answer 2

example of GMP signaling

• process begins with G_qα signaling
• calmodulin activated eNOS (endothelial nitric oxide synthase) -> produces NO, which diffuses from endothelial cells to SMCs
• NO then activates a guanylyl cyclase, which produces cGMP -> activates protein kinase G
• PKG phosphorylates a number of targets, some of which lead to a reduction in cytoplasmic [Ca²⁺] -> vasodilation (smooth muscle relaxation)

pg 505

Question 3

treatments for erectile dysfunction

Answer 3

• goal is to block cGMP phosphodiesterase which converts cGMP to inactive 5-GMP
• drugs like viagra inhibit the enzyme causing cGMP levels to remain elevated and blood vessels to remain dilated leading to longer lasting erection

pg 506

Question 4

nuclear receptors

Answer 4

• intracellular receptors
• two major classes
• dual-function proteins: hormone receptors and transcription factors

pg 508

Question 5

type I nuclear hormone receptors

Answer 5

• bound to Hsp70 in cytosol in absence of ligand
• hormone binding induces a conformational change, which causes dissociation from Hsp70
• most often form homodimers (two identical proteins bound to each other)
• can be inhibited by IncRNAs -> although this is NOT unique to type I NHRs
• glucocorticoids, androgens, estrogens
• Tamoxifen – Estrogen receptor antagonist –Cancer therapy
• Mifepristone – Progesterone receptor antagonist – Contraceptive & Early pregnancy termination (before wk 10)

pg 509

Question 6

type II nuclear hormone receptors

Answer 6

• bound to DNA and corepressor proteins in the absence of ligand (these receptors are sent to nucleus immediately after translation)
• ligand binding includes a conformation change, which kicks off corepressors and brings in coactivators
• most often form heterodimers with the retinoid X receptor (RXR)
• thyroid hormone

pg 510

Question 7

gated ion channels

Answer 7

• provide maintenance of electrial gradient
• a lot of cells NEED these channels as they rely on excitability for their function
• electrogenic Na+K+ATPase pump produces a transmembrane potential of 60 mV (inside is negative)
• chemical gradient of Na+ and Ca2+ drives them inward (depolarization) and K+ outward (hyperpolarization)
• electrical gradient drives Cl- outward against its concentration gradient (depolarization)

pg 512

Question 8

voltage-gated ion channels in neuronal action potential

Answer 8

• plasma membrane of the pre-synaptic neuron is polarized (negative inside)
• stimulus to the neuron causes an action potential to move along the axon -> opening of 1 voltage gated Na+ channel allows Na+ entry, local depolarization causes adjacent Na+ channels to open (directionality ensured by refractory period)
• wave of depolarization reaches axon tip -> voltage gated Ca2+ channels open allowing Ca2+ entry
• increase in internal [Ca2+] triggers exocytic release of acetylcholine into the synaptic cleft
• acetylcholine binds to a receptor on postsynaptic neuron causing its ligand-gated ion channel to open -> Na+ and Ca2+ enter depolarizing the postsynaptic neuron

pg 513

Question 9

eicosanoids signaling

Answer 9

• local paracrine signaling, fatty acid based
• four major classes of eicosanoids: prostaglandins, thromboxanes, leukotrienes, lipoxins
• derived from diet or membrane phospholipids
• major precursors include linoleic acid, linolenic acid, and arachidonic acid
• most function as ligands for GPCRs (eicosanoids undergo a GPCR mechanism)
• major functions: inflammation, pain, fever, gastric acid secretion, blood clotting, platelet aggregation

pg 516

Question 10

major regulation of phospholipase A₂

Answer 10

• phospholipase A2 converts a phospholipid to arachidonic acid to form the eicosanoids
• activated by BOTH Ca2+ and phosphorylation from a MAPK protein
• expression inhibited by glucocorticoids

pg 517

Question 11

the COX pathway

Answer 11

• COX = cyclooxygenase
• COX1 and COX2 major players in PGH2 production
• gives rise to prostaglandins and thromboxanes (collectively called “prostanoids”) -> from arachidonic acid
• target of anti-pyretic (fever -> decrease temp) and anti-pain drugs

pg 518

Question 12

PGE2

Answer 12

• created through the COX pathway
• acts on hypothalamus to increase body temperature in response to inflammation

Question 13

common OTC pain meds target COX enzymes

Answer 13

• aspirin: suicide inhibitor of COX
• acetaminophen and ibuprofen: competitive inhibitors of COX
• side effects: COX enzymes are involved in mucus production in the stomach (can cause ulcers by blocking mucin production)

pg 519

Question 13

prostaglandins and thromboxanes

Answer 13

created through the COX pathway

• prostaglandins: responsible for pain, fever, inflammation
• thromboxanes: platelet aggregation, blood clots
• both inhibited by COX inhibitors

Question 14

the lipoxygenase pathway: leukotrienes

Answer 14

• 5-lipoxygenase is a major player (helps convert arachidonic acid to leukotrienes which are produced in leukocytes)
• gives rise to cysteinyl leukotrienes -> LTC4, LTD4, LTE4, LTF4
• CysLTs involved in a number of processes, including vascular and bronchial smooth muscle contraction(can lead to asthma attacks), many others
• lipoxins: anti-inflammatory roles (type of eicosanoid)

pg 520

Question 15

eicosanoids, class, and function

Answer 15

LTC4, LTD4, LTE4 -> contract vascular and bronchial smooth muscle, stimulate mucus secretion in airway and gut -> block these eicosanoids and may have relief from asthma attacks

pg 521

Question 16

drug names, targets, relevance

Answer 16

• prednisone: binds to glucocorticoid receptor to influence gene transcription -> cools inflammation by inhibiting phospholipase A2 and transcription of COX-2
• aspirin: irreversibly acetylates and inactivates COX-1 and COX-2 -> pain and inflammation relief, long term prophylaxis for heart attacks
• ibuprofen/naproxen: competitive inhibition of COX-1 and COX-2 -> pain and inflammation relief
• celebrex: competitive inhibition of COX-2 (more gastric side effects) -> pain and inflammation relief
• acetaminophen: may function to inhibit COX activity in the CNS specifically -> pain, fever relief (no anti-inflammatory effects)
• singulair: antagonist of CysLT (leukotriene) receptors -> asthma and allergic bronchitis relief
• zyflo: 5-Lox inhibitor, blocks production of ALL leukotrienes -> prophylactic anti-asthma therapy

pg 522