Medical Physiology Boron Pdf
Regulation of intracellular pH, gas channels We have three major research areas (see below). These evolved from our longstanding interest in intracellular pH (pH i) homeostasis, which is critically important because virtually every biological process—cell division, metabolism, action of channels/transporters/structural proteins—depends on pH i. Our three projects interact philosophically and technically. Mio Black Edition (n191) Action Pack. Philosophically, pH i homeostasis depends on HCO 3 − and H + transport across cell membranes, which in turn depends on pH, [CO 2] and [HCO 3 −] in the extracellular (o) fluid. The kidneys regulate pH o by regulating [HCO 3 −] o—and they do this by using novel sensors to sniff CO 2 and HCO 3 − in the blood. The lungs, controlled by brainstem neurons, regulate pH o by regulating [CO 2] o.
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The whole system depends on movements of CO 2 (and other gases) through gas channels in the cell membrane. Technically, our projects exploit technologies ranging from structural biology, through molecular and cell physiology, to whole tissues and organisms. Homeostasis of intracellular pH As a graduate student, I imposed acute intracellular acid loads and found that the sudden pH i decrease is followed by a recovery—the first demonstration of pH i regulation. Castlevania Curse Of Darkness Ps2 Torrent on this page. Later work showed that this recovery is mediated by a Na +-driven Cl-HCO 3 exchanger (NDCBE)—the first documented pH i regulator. As a fellow, we identified the electrogenic Na/HCO 3 cotransporter (NBCe1), which not only regulates pH i but also mediates HCO 3 − movement of across many epithelia. Since cloning the cDNA encoding NBCe1, our group has studied the molecular mechanism of Na +-coupled HCO 3 − transporters (NCBTs)—members of the SLC4 family of transport proteins. For example, emerging data indicate that NBCe1 and NDCBE—expressed in Xenopus oocytes—transport CO 3 = rather than HCO 3 −.
Carbonic anhydrases do not change transport rate but stabilize surface pH. Chimera making shows that extracellular loop #4 is critical for determining electroneutrality vs electrogenicity. Certain splice variants have autoinhibitory or autostimulatory domains.
The large cytoplasmic N terminus of NBCe1 binds to and thereby activates the transmembrane domain. Finally, we are producing large quantities of NBC-related proteins to study their molecular biophysical properties. Sensors for extracellular CO 2 and HCO 3 − While studying isolated, perfused proximal tubules (PTs), we noticed that adding CO 2/HCO 3 − to the PT's basolateral (BL or blood) side causes pH i to increase, reflecting stimulated H + extrusion across the apical membrane (facing lumen). To elucidate the mechanism, we invented out-of-equilibrium (OOE) CO 2/HCO 3 − solutions, which allow us to vary [CO 2] BL, [HCO 3 −] BL, and pH BL—one at a time. We found that isolated increaes in [CO 2] BL or isolated decreases in [HCO 3 −] BL stimulate H + secretion into the tubule lumen ( J H).
Surprisingly, acute changes in pH BL have no effect on J H! Thus, the tubule regulates blood pH by sensing not pH but the two major blood buffers. The signal-transduction system linking basolateral CO 2 and HCO 3 − to apical H + extrusion involves: (1) Apical AT 1 (angiotensin II, ANG II) receptors and ANG II that the tubule secretes into the lumen.
(2) Tyrosine phosphorylation. Inhibitors of ErbB receptor tyrosine kinases block responses to basolateral CO 2 or HCO 3 −. The same is true for knockout of receptor protein tyrosine phosphatase γ (RPTPγ), in which the extracellular ligand-binding region is an inactive carbonic-anhydrase-like domain (CALD). We are testing the hypothesis that the CALD is the sensor for extracellular CO 2 and HCO 3 −. We are also using biochemical approaches to explore signal transduction. Gas channels While studying pH i regulation in gastric parietal cells we found that the apical membrane has no detectable permeability to either CO 2 or NH 3—the first documented gas-impermeable membrane. This led us to rethink “Overton’s rule” and to describe the first gas channel aquaporin 1 (AQP1), which is not only permeable to H 2O but also CO 2. Others later showed that AQP1 is permeable to NH 3, and that the rhesus (Rh) proteins are permeable to CO 2 and NH 3. We developed an approach for using a large pH microelectrode to monitor the extracellular surface pH (pH S) on Xenopus oocytes exposed to CO 2 or NH 3.
Initial pH S transients are indices of CO 2 or NH 3 permeability. Studying a wide range of AQPs and Rh proteins, we see that each has a characteristic CO 2/NH 3 permeability ratio—the first example of gas selectivity.