Teodor Paunescu, PhD

Paunescu Laboratory

The Teodor Paunescu Laboratory studies proton secretion in the kidney and the olfactory epithelium, and its relevance for maintaining body acid-base balance, the sense of smell, and nutrition.

Overview

Our laboratory examines the regulation of transepithelial transport, focusing on the biology and (patho) physiology of the vacuolar proton-pumping ATPase (V-ATPase) in the kidney and other epithelia. By acidifying the extracellular environment, the V-ATPase plays a crucial role in maintaining healthy organ function and is perturbed in numerous pathological conditions. The V-ATPase is a key player in physiological processes such as acid-base homeostasis, male fertility, bone remodeling, and hearing.

The V-ATPase 56-kDa B subunit occurs in mammalian tissues as two homologous isoforms, Atp6v1b1, or "B1" (highly expressed in a restricted number of epithelia specialized for regulated H+ transport), and the ubiquitous Atp6v1b2 (“B2”) isoform. In renal collecting duct A-type intercalated cells (ICs), the B1 isoform localizes to the apical membrane and subapical domain, whereas B2 localization is less polarized. This is consistent with B1-containing V-ATPases being involved in regulated transmembrane H+ transport and B2-containing enzymes being responsible mostly for the acidification of intracellular organelles. Under certain conditions, B2-containing V-ATPase holoenzymes can be detected on the cell membrane and can mediate H+ secretion, such as in mice deficient in the B1 isoform. Understanding the mechanisms and stimuli leading to B1 and/or B2 assembly into the V-ATPase complex, and their role in V-ATPase trafficking and regulation, could offer treatment strategies for pathologies that result from loss or disruption of B1 subunit function. In general, understanding how epithelial cells respond to various stimuli by modulating the trafficking of transport proteins to and from the plama membrane is essential in approaching all diseases underlined by trafficking defects, including nephrogenic diabetes insipidus, polycystic kidney disease, cystic fibrosis, and many others.

We found that the V-ATPase is also highly expressed in the olfactory epithelium (OE). The B1 subunit isoform localizes to the apical microvilli of sustentacular cells and to the lateral membrane domain in microvillar cells. As a mediator of H+ secretion in the OE, the V-ATPase may be important for the pH homeostasis of the neuroepithelial mucous layer and/or for signal transduction in the sense of olfaction. Functional data from innate avoidance and appetitive behavior tests confirm the relevance of this enzyme in olfaction. We are now pursuing translational and clinical applications of these basic science findings, by investigating olfactory defects in kidney patients. Our goal is to develop strategies to improve these patients’ olfactory function and nutritional status.

Publications

  1. Păunescu TG*, Da Silva N*, Marshansky V, McKee M, Breton S, Brown D. Expression of the 56-kDa B2 subunit isoform of the vacuolar H(+)-ATPase in proton-secreting cells of the kidney and epididymis Am J Physiol Cell Physiol 2004; 287(1): C149-162.
  2. Finberg KE, Wagner CA, Bailey MA, Păunescu TG, Breton S, Brown D, Giebisch G, Geibel JP, Lifton RP. The B1-subunit of the H(+) ATPase is required for maximal urinary acidification. Proc Natl Acad Sci USA 2005; 102(38): 13616-13621.
  3. Păunescu TG, Da Silva N, Russo LM, McKee M, Lu HA, Breton S, Brown D. Association of soluble adenylyl cyclase with the V-ATPase in renal epithelial cells. Am J Physiol Renal Physiol 2008; 294(1): F130-138.
  4. Păunescu TG, Jones AC, Tyszkowski R, Brown D. V-ATPase expression in the mouse olfactory epithelium. Am J Physiol Cell Physiol 2008; 295(4): C923-930.
  5. Păunescu TG*, Ljubojevic M*, Russo LM, Winter C, McLaughlin MM, Wagner CA, Breton S, Brown D. cAMP stimulates apical V-ATPase accumulation, microvillar elongation, and proton extrusion in kidney collecting duct A-intercalated cells. Am J Physiol Renal Physiol 2010; 298(3): F643-F654.
  6. Păunescu TG, Rodriguez S, Benz E, McKee M, Tyszkowski R, Albers MW, Brown D. Loss of the V-ATPase B1 subunit isoform expressed in non-neuronal cells of the mouse olfactory epithelium impairs olfactory function. PLoS ONE 2012; 7(9): e45395.
  7. Vedovelli L, Rothermel JT, Finberg KE, Wagner CA, Azroyan A, Hill E, Breton S, Brown D, Păunescu TG. Altered V-ATPase expression in renal intercalated cells isolated from B1-subunit deficient mice by fluorescence activated cell sorting. Am J Physiol Renal Physiol 2013; 304(5): F522-F532.
  8. Păunescu TG, Shum WWC, Huynh C, Lechner L, Goetze B, Brown D, Breton S. High-resolution helium ion microscopy of epididymal epithelial cells and their interaction with spermatozoa. Mol Human Reprod 2014; 20(10): 929-937.
  9. Merkulova M, Păunescu TG, Azroyan A, Marshansky V, Breton S, Brown D. Mapping the H(+) (V)-ATPase interactome: identification of proteins involved in trafficking, folding, assembly and phosphorylation. Sci Rep 2015; 5:14827.

Contact

Contact Us

Teodor Paunescu, PhD

CPZN 8.220

185 Cambridge Street Boston, MA 02114
  • Phone: 617-643-3180
  • Fax: 617-643-3182
  • Email Us

Assistant Professor of Medicine

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