Our research focuses on the vacuolar proton-pumping ATPase (V-ATPase), and in particular on the role of its B subunit isoforms in the physiology and pathophysiology of H+ secretion.

Teodor G. Paunescu, PhD 
Instructor of Medicine 
185 Cambridge Street, CPZN 8.150
Boston, MA 02114
Phone: (617) 726-3696
Fax: (617) 726-5669
Email: Paunescu.Teodor@mgh.harvard.edu

 

Our research focuses on the vacuolar proton-pumping ATPase (V-ATPase), and in particular on the role of its B subunit isoforms in the physiology and pathophysiology of H+ secretion. The V-ATPase plays an essential role in numerous membrane trafficking processes by mediating the acidification of intracellular organelles. When expressed in the plasma membrane domain , the V-ATPase mediates active H+ transport into, and the pH regulation of, extracellular compartments. The V-ATPase 56kDa 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, including the urogenital tract, the inner ear, eye, respiratory and olfactory epithelia), and the ubiquitous Atp6v1b2 (B2) isoform.

Area (A) of Research:

In renal collecting duct A-type intercalated cells, we found that the V-ATPase B1 subunit 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 for the acidification of intracellular organelles. We showed that 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.

Area (B) of Research:

A new avenue of research was recently opened when we discovered that the V-ATPase is expressed in the olfactory epithelium (OE). Its localization pattern suggests that V-ATPase-mediated H+ secretion is important for CO2 and odor detection, and preliminary data from home-cage habituation-dishabituation tests and two-chamber CO2 aversion experiments support these hypotheses. We consequently aim at elucidating the mechanisms and physiological relevance of V-ATPase-mediated H+ secretion in the OE. The clinical significance of this project ranges from mitigating olfactory function loss due to aging or disease (such as Alzheimer's disease or end stage renal disease) to acquiring the ability of up- or down-regulating the threshold of detection for certain odorants via modulating V-ATPase-mediated olfactory H+ secretion.

 

References:

  1. Brown D, Paunescu TG, Breton S, Marshansky V. Regulation of the V-ATPase in kidney epithelial cells: dual role in acid-base homeostatis and vesicle trafficking. J. Exp. Biol. 2009 Jun. 212(11): 1762-1772.
  2. Paunescu TG, Jones AC, Tyszkowski R, Brown D. V-ATPase expression in the mouse olfactory epithelium. Am J Physiol Cell Physiol. 2008 Oct. 295(4): C923-930.
  3. Paunescu 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 Jan. 294(1): F130-138.
  4. Paunescu TG, Russo LM, Da Silva N, Kovacikova J, Mohebbi N, Van Hoek AN, McKee M, Wagner CA, Breton S, Brown D. Compensatory membrane expression of the V-ATPase B2 subunit isoform in renal medullary intercalated cells of B1-deficient mice. Am J Physiol Renal Physiol. 2007 Dec. 293(6): F1915-1926.
  5. Finberg KE, Wagner CA, Bailey MA, Paunescu 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 Sept. 102(38): 13616-13621.
  6. Paunescu 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 Jul. 287(1): C149-162.