APPH 6211 Systems Physiology I: Cellular mechanisms of plasticity

1. APPH 6211 Systems Physiology I:Cellular mechanisms of plasticity • Text: Cell Biology Updated Edition.T.D. Pollard, & W.C. Earnshaw, eds Elsevier (2004) ISBN 1-4160-23887 Saunders (2007) ISBN 978-1416022558 • Instructor: Tom Burkholder555/575 14th St, 1309F, 4-1029, thomas.burkholder@hps.gatech.edu • On-campus hour: • Exam: (Tentative) Sep 19, Oct 10, Nov 7, Dec 12 • Online Syllabus & Readings: http://www.ap.gatech.edu/Burkholder/6211/ • Other references W. Boron, E.L. Boulpaep Medical Physiology B. Alberts et al. Molecular Biology of the Cell http://www.ncbi.nlm.nih.gov/books/NBK21054/ D. Silverthorn Human Physiology

2. Policies • Honor code • Closed-book exams • No make-up exams • Class attendance optional

3. Special Challenges • Engineers • Be prepared to work • APPH/BIOL 3751 BIOL 4446 BMED 3160 • Biochemistry • Generic cellular mechanisms • Specific physiological applications • Project

4. Controller Plant Sensor Cellular processes as dynamical systems • Plant – performs some physiological function • Controller – changes rate/efficiency of plant • Sensor – monitors effectiveness of plant • Homeostasis – tendency to maintain an internal state • Stability of the dynamical system

5. Physiological Themes • Homeostasis • Negative feedback - stable • Steady-state condition (usually non-equilibrium) • Sensors & controls • Excitability • Positive feedback - unstable • Energy storage & release • Communication • Plasticity • Change that brings about homeostasis • Temporal hierarchy

6. Cell structure • Cytoplasm • Organelles • Nucleus • Endoplasmic reticulum • Golgi apparatus • Mitochondria • Protein complexes • ORC • Transcription complexes • Ribosome • Proteasome

7. Information coding model • Gene • Intron/exon • Promoter • Remote regulatory regions • RNA • m/t/r • Transcription • Alternative splicing • Translational regulation • Protein Central dogma Flippantly coined by Francis Crick in the 1950s, which he and Watson would come to despise for its misinterpretation. They meant it for the idea that information flows from nucleic acids to proteins and never backwards.

8. Protein • Structure • Modular domains • Structure/shape • Chemical properties • Co-translational modifications • Function • Structure • Synthesis • Transport • Post-translational modification

9. Model systems • Posture (BB 9, 12-14) • Muscle force generation • Neural regulation • Blood homeostasis (BB 32-39) • Glomerular filtration • Hormonal regulation

10. Blood homeostasis • Volume/pressue homeostasis • Composition homeostasis • Kidney function • Osmotic regulation • Hormonal regulation • Neural regulation

11. Kidney function • Free fluid transfer from capillaries to Bowman’s capsule • 70 nm epithelial cell fenestrations • Mechanical filter only • Fluid reabsorption in proximal tubule • Osmotically powered by NaCl transport • Also HCO3-, Ca2+, etc • Osmotic balancing in Loop of Henle • Final polishing in distal tubule/collecting duct

12. Glomerular Blood flow Fluid removal Distal Tubule Na+ Control of glomerular filtration • Fluid mechanics • Physical pressure in glomerular capillaries • Osmotic pressure • 125 ml/min! • Myogenic response • Tubuloglomerular feedback

13. Control of proximal tubule reabsorption • Proximal tubule • Na+ driven cotransporters lumenal • Active transport of Na+ basolateral • Glomerulotubular balance • Reabsorption of constant Na+ fraction • Dialysis of filtrate against remaining fluid • Hormonal regulation (hypothalamus) • Endogenous ATPase inhibitor • Blocks NaK Systemic [Na+] Na+ reabsorption Endogenous ATPase inhib

14. Na+ reabsorption Circulating volume Aldosterone Neural control of filtration • Collecting duct • Final polishing of urine • 2-3% Na+ reabsorption • Sympathetic NS • Norepinepherine • Vasoconstriction reduces GFR • Renin-Aldosterone stimulation • Increases Na+ reabsorption • Thirst

15. Cellular aspects of blood homeostasis • Kidney • Hemodynamics • Channel kinetics • Pump activity • Chemical sensors • Monitoring of electrolytes, organic solutes • Local control • Sympathetic nervous system • Monitoring of “global” parameters • Signal processing • Coordinated control

16. CoM Posture • Maintain body configuration • Intrinsic instability • Extrinsic perturbation • Control loops • Intrinsic (muscle) • Peripheral (spine) • Central (brainstem & cortex) Inverted pendulum model of posture

17. Crossbridge binding a=F/m Filament overlap Intrinsic control of posture • Sarcomere • Interdigitating filament matrices • Crossbridge • Elasticity • Viscosity • Control derived from autonomous behavior Sarcomere structure Tension step response

18. Motor neuron recruitment a=F/m Spindle firing Peripheral control of posture • Muscle spindle • Specialized muscle fibers • Sensory afferent • Length & velocity sensor • Motor neuron • Controls many fibers • Stimulated by spindle afferent • Control derived from communication between cells

19. Central control of posture • Vestibular system • Semicircular canals – angular acceleration • Otolith organs – linear acceleration • Cerebellum • Integrates multiple sensory systems • Forms whole body model • Organizes response • Control derived from information outside the immediate effector

20. Cellular aspects of postural control • Muscle • Regulation of force generation • ATP homeostasis • Force capacity homeostasis • Spindle • Monitoring of physical stimuli • Rapid communication • Motor neuron • Signal processing • Rapid communication • Learning