Unit 4 Flashcards
Describe the key events involved in muscle contraction (starting from neuromuscular transmission and ending with contraction of the muscle)
-Lawlor
- Acetylcholine is released into the neuromuscular junction and activates Na+ channels, which initiates an action potential that moves down the T-tubule.
- The AP triggers the voltage-gated Ca2+ channel, DHPR, which, in turn, activates the RyR calcium channel, thereby releasing Ca2+ from the star opals is reticulum.
- Ca2+ binds troponin, causing a conformation change to tropomyosin, which frees cross-bridge binding sites on actin.
- Myosin-bound ATP is hydrolysis to ADP + Pi, causing myosin head extension and binding to actin.
- Myosin pulls actin toward the M-line (powerstroke) to shorten the sarcomere (contraction).
- ADP + Pi are released and ATP binding releases myosin from actin.
Explain two disease states that illustrate dysfunction in the muscle contraction process.
-Lawlor
Myasthenia Gravis:
- autoimmune disease where antibodies block acetylcholine receptors in the neuromuscular junction, thereby preventing the formation of action potentials & ultimately muscle contraction.
Myotubular myopathy:
- caused by loss of myotubularin (MTM1), a triad component. Results in small mayo fibers, organelle mislocalization, and triad loss.
Extracellular and intracellular ionic composition (Na+, K+, and Ca2+)
-Kwok
Na+ - outside
- 140 mM extracellular
- 10 mM intracellular
K+ - inside
- 4 mM extracellular
- 140 mM intracellular
Ca2+ - outside
- 2.4 mM extracellular
- 50 nM intracellular
What forces determine what direction ions will go?
-Kwok
Electrical forces (positive and negative charges) and chemical forces (concentration gradients).
Electrical forces = chemical forces —> no flux, @ equilibrium
Ventricular action potential
-Kwok
phase 0: Na+ influx
- depolarization
- INa
phase 1: K+ influx
- ITO (K+)
phase 2: Ca2+ influx
- plateau phase
- delicate balance/easily perturbed
- allows Ca2+ to come in and cell contracts
phase 3: K+ efflux
- repolarization
- IK
phase 4:
- resting state
SA node action potential
-Kwok
SA node does not use sodium for depolarization, it uses calcium!
Calcium channels open slower so get slower depolorization.
Atrial and ventricle: depoloraization due to sodium
Nodal tissue: depolorization due to calcium
Sodium channels
-Kwok
- responsible for ventricle/atrium phase 0 depolarization
Structure:
- 4 domains, each with 6 transmembrane segments
- Loops between S5 and S6 line interior of pore
- makes channel permeable to sodium
- S4 (red) is voltage center
- makes channel sensitive to voltage
- cytosolic linker between D3 and D4 important for inactivation
Inactivation:
- inactivation loop swings over and blocks pore
- recovery is time and voltage dependent.
- membrane potential more negative than -60 mV facilitates transition from inactivated to closed state
Calcium channels
-Kwok
- influx during phase 2 plateau
- balanced by K+ efflux to determin AP duration
- causes intracellular calcium-induced calcium-release from SR to increase intracellular calcium and induce contractile process
- nodal cells use calcium channels for depolarization (NOT sodium channels)
Structure:
- 4 domains with 6 transmembrane regions
- S4 region = voltage sensing
- S5 and S6 linker region = selectivity loop, lines pore
Inactivation
- Ca2+ dependent inactivation
- Fast voltage-dependent inactivation
- Slow votlage-dependent inactivation
Potassium channels
-Kwok
Delayed rectifier isoforms:
- Similar to one domain of Ca2+ or Na+ channel
- 4 domains form channel (tetramer)
- critical for repolorazation
- Slowly activating - IKs
- Rapidly activating - IKr
Inward rectifier isoform (IK1)
- equivalent to S5/S6 (pore) region of delayed rectifier
- no voltage sensor
- forms tetramers
- late phase 3 repolarization
- open @ rest
- allows efflux of K+, which is why resting potential is -90 mV
Long QT Syndrome
-Kwok
Prolonged action potenial
- as begins repolarizaing, allows Na channels to be reactivated from inactivation state
- triggers action potenials when it shouldn’t
Atherosclerosis
-Pfister
- Fatty material (plaque) builds up arteries
Stages of atherosclerosis
- Endothelial dysfunction
- endothelium has increased permeability to lipoproteins
- upregulation of endothelial adhesion molecules
- leukocytes migrate into artery wall
- Fatty-streak formation
- Advanced, complicated lesions
- fibrous cap walls of lesion from the lumen
- covers a mixture of leukocytes, lipid, and debris
- Unstable fibrous plaques
- rupture of fibrous cap
Cholesterol Function and Synthesis
-Pfister
Function:
- cell growth and development
- building blocks for membranes
- synthesis for steroid hormones, bile acids, and vitamin D
Synthesis:
- from acetyl-coA
- rate limiting step:
- HMG-CoA reductase
Regulation of HMG-CoA Reductase
-Pfister
- transcription
-
SREBP: transcription factor
- SREBP binds SCAP to form SCAP-SREP complex that is a sterol sensor in ER
- When sterol levels are high, Insig proteins bind SCAP to keep in ER
- When sterol levels are low, SCAP-SREP complex translocate to Golgi and SREBP is cleaved
- bHLH-SREBP domain enters nucleus and binds and promotes transcription of an SRE
-
SREBP: transcription factor
- translation
- HMG-CoA translation inhibited by nonsterol metabolites from mevalonate, dietary cholesterol, and oxysterols
- degradation
- HMG-CoA binds insigs associated with ubiquitin
- ubiquitination
- phosphorylation
- phosphorylation INACTIVATES
- hormonal regulation
- insulin causes increased synthesis
- glucagon causes decreased synthesis
Cholesterol circulation
-Pfister
Cholesterol is nonpolar. Need to solubilize to be in blood!
LIPOPROTEINS
- core of non-polar lipids
- monolayer of exterior phospholipids
- integral and peripheral apoproteins
Apolipoproteins
- help solubilize the lipoprotein
- activate/inhibit plasma enzymes
- binding sites for cell surface receptors
Lipoprotein types
-
Chylomicrons
- triglyceride-rich
-
Very low density lipoproteins
- triglyceride-rich
-
Low density lipoproteins
- cholesterol-rich
-
High density lipoproteins
- cholesterol-rich
Chylomicrons
-Pfister
Dietary lipids go to small intestine where they are packaged into chylomicrons and circulate through blood stream.
Lipoprotein lipase (LPL) hydrolyzes triglycerides into free fatty acids, which can be used by muscle for energy or stored as adipose tissue.
Chylomicron remmnant retains cholesterol, which is taken to the liver.
Major lipid composition: triglycerides
Major apoprotein: apoB48
Major effect: carries dietary cholesterol to liver and packages dietry triglycerides for LDL hydrolysis to free fatty acids for storage or energy