Lecture 21 Flashcards
Cell Signaling III
1
Q
introduction to receptor guanyl cyclases
A
- 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
2
Q
acetylcholine induced vasodilation
A
example of GMP signaling
- process begins with Gqα 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
3
Q
treatments for erectile dysfunction
A
- 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
4
Q
nuclear receptors
A
- intracellular receptors
- two major classes
- dual-function proteins: hormone receptors and transcription factors
pg 508
5
Q
type I nuclear hormone receptors
A
- 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
6
Q
type II nuclear hormone receptors
A
- 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
7
Q
gated ion channels
A
- 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
8
Q
voltage-gated ion channels in neuronal action potential
A
- 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
9
Q
eicosanoids signaling
A
- 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
10
Q
major regulation of phospholipase A2
A
- 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
11
Q
the COX pathway
A
- 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
12
Q
PGE2
A
- created through the COX pathway
- acts on hypothalamus to increase body temperature in response to inflammation
13
Q
common OTC pain meds target COX enzymes
A
- 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
13
Q
prostaglandins and thromboxanes
A
created through the COX pathway
- prostaglandins: responsible for pain, fever, inflammation
- thromboxanes: platelet aggregation, blood clots
- both inhibited by COX inhibitors
14
Q
the lipoxygenase pathway: leukotrienes
A
- 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
