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Muscle Spindles

Muscle Spindles. “fusus” is the latin word for “spindle”. muscle innervation. As with outer hair cells in the inner ear, organisms commonly vary the sensitivity of mechanotransducers, and exploit rapid adaptation to generate first derivative outputs. .

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Muscle Spindles

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  1. Muscle Spindles

  2. “fusus” is the latin word for “spindle”

  3. muscle innervation As with outer hair cells in the inner ear, organisms commonly vary the sensitivity of mechanotransducers, and exploit rapid adaptation to generate first derivative outputs.

  4. Coste et al (2010) Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels. Science 330, 55-60. • Very few mechanically activated (MA) ion channels have been clearly identified to date, despite the importance of mechanotransduction for touch, pain, hearing, kidney flow sensing, proprioception, embryonic development, lung growth and injury, bone and muscle homeostasis, blood flow and vascular tone. • These workers tested various mouse and rat cell lines for MA currents, applying force to the cell surface while patch clamping using the whole cell configuration. • The N2A mouse neuroblastoma cell line showed the most consistent responses, with the fastest adaptation kinetics to sustained stimulation.

  5. Coste et al (2010) Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels. Science 330, 55-60. • They searched for transcripts enriched in N2A cells using microarrays, selecting proteins predicted to span the membrane at least twice, and prioritising known cation channels and proteins with unknown function. • Candidate genes expressed in N2A cells were tested using siRNA knockdown, checking that the MA currents disappeared. • Two genes were identified Piezo1 and Piezo2. • These authors showed that Piezo1 is directed to the plasma membrane, and that Piezo1 and Piezo2 transfection induces MA currents in other cell types.

  6. Coste et al (2010) Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels. Science 330, 55-60. (A) Representative traces of MA inward currents expressed in N2A cells. Cells were subjected to a series of mechanical steps of 1-mm movements of a stimulation pipette (inset illustration, arrow) in the whole-cell patch configuration at a holding potential of –80 mV. (B) Average current-voltage relationships of MA currents in N2A cells (n = 11 cells). (Inset) Representative MA currents evoked at holding potentials ranging from–80 to +40mV (applied 0.7 s before the mechanical step).

  7. Coste et al (2010) Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels. Science 330, 55-60. (C) Single-channel currents (cell attached patch configuration) induced by means of negative pressure with a pipette (inset illustration, arrow) at holding potentials ranging from –80 mV to +80 mV in a N2A cell. (D) Average current-voltage relationships of stretch activated single channels in N2A cells (n = 4 cells, mean T SEM). Single channel conductance was calculated from the slope of the linear regression line of each cell, giving g = 22.9 T 1.4 pS (mean T SEM). Single-channel amplitude was determined as the amplitude difference in Gaussian fits of full-trace histograms.

  8. Coste et al (2010) Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels. Science 330, 55-60. (E) Representative currents (averaged traces) induced by means of negative pipette pressure (0 to –60 mmHg, D 10 mmHg) in a N2A cell. (F) Normalized current-pressure relationship of stretch-activated currents at –80 mV fitted with a Boltzmann equation (n = 21 cells). P50 is the average value of P50 values from individual cells.

  9. Coste et al (2010) Science 330, 55-60.

  10. Xiao & Xu (2010) Mechanosensitive Channels: In Touch with Piezo. Current Biology 20, R936-R937.

  11. Baroreceptors & chemoreceptors • Receptors on the aortic arch and carotid arteries report on the pressure and oxygenation of the blood • Baroreceptor stimulation causes reflex bradycardia, which helps to stabilise the blood pressure • The chemoreceptors are tiny, but with very high blood flow • Chemoreceptor stimulation by low oxygen increases respiratory effort

  12. Park et al (2009) Am J Physiol 297, C855-C864Kreniesz et al (2009) J Physiol 587, 5819-5830 • In 2004 and 2005 it was reported that heme oxygenase was the oxygen sensor, and the second messenger was carbon monoxide. • Gene knockout experiments subsequently showed that this was not the case. • Park et al (2009) suggest that oxygen binds to NADPH oxidase, changing its conformation. This haem enzyme binds to TASK-1 and TASK-3 potassium channels and provides a major part of the signal. • Kreniesz et al (2009) argue that AMPK phosphorylation of TREK-1 and TREK-2 also contributes to this.

  13. AMPK • AMPK = AMP-dependent protein kinase, which is often referred to as the “cellular fuel gauge”. • This works with linear 5’AMP formed by the myokinase reaction: ATP + AMP = ADP + ADP Keq = 1 [AMP] = [ADP]2 / ATP • High [AMP] means there is low cellular energy supply. • AMPK is NOT the same as 3’5’ cyclic AMP dependent protein kinase, or PKA, which is involved in many GPCR signalling mechanisms.

  14. Pluznick et al (2009) Functional expression of the olfactory signaling system in the kidney. PNAS 106, 2059-2064 • Major components of olfaction, including olfactory receptors (ORs), olfactory-related adenylate cyclase (AC3) and the olfactory G protein (Golf), are expressed in the kidney. • AC3 and Golf colocalize in renal tubules and in macula densa (MD) cells which modulate glomerular filtration rate (GFR). • GFR is significantly reduced in AC3-/- mice, suggesting that AC3 participates in GFR regulation. • Although tubuloglomerular feedback is normal in these animals, they exhibit significantly reduced plasma renin levels despite up-regulation of COX-2 expression and nNOS activity in the MD. • At least one member of the renal repertoire of ORs is expressed in a MD cell line. • Key components of olfaction are expressed in the distal nephron and may play a sensory role in the MD to modulate both renin secretion and GFR.

  15. revision advice • This is a huge field. Therefore we will not set questions that depend on knowing obscure details of one particular sensor. • We will set general questions about broad themes, but expect you to provide specific examples to illustrate your answer. • We advise you to read one or two papers or reviews in each topic area, covering a range of species.

  16. end of the slide show now switch to the course website at http://www.bmb.leeds.ac.uk/illingworth/bioc3800/index.htm and visit some relevant websites and published papers

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