[GRG] Proton pump may work both ways – Rockefeller U.

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Route, mechanism, and implications of proton import during Na+/K+
exchange by native Na+/K+-ATPase pumps

Natascia Vedovato and
David C. Gadsby

+
Author Affiliations
The Laboratory of Cardiac/Membrane Physiology, The Rockefeller
University, New York, NY 10065
Correspondence to David C. Gadsby: gadsby@rockefeller.edu

Abstract

A single Na+/K+-ATPase pumps three Na+ outwards and two K+ inwards
by alternately exposing ion-binding sites to opposite sides of the
membrane in a conformational sequence coupled to pump
autophosphorylation from ATP and auto-dephosphorylation. The larger
flow of Na+ than K+ generates outward current across the cell
membrane. Less well understood is the ability of Na+/K+ pumps to
generate an inward current of protons. Originally noted in pumps
deprived of external K+ and Na+ ions, as inward current at negative
membrane potentials that becomes amplified when external pH is
lowered, this proton current is generally viewed as an artifact of
those unnatural conditions. We demonstrate here that this inward
current also flows at physiological K+ and Na+ concentrations. We
show that protons exploit ready reversibility of conformational
changes associated with extracellular Na+ release from
phosphorylated Na+/K+ pumps. Reversal of a subset of these
transitions allows an extracellular proton to bind an acidic side
chain and to be subsequently released to the cytoplasm. This back-
step of phosphorylated Na+/K+ pumps that enables proton import is
not required for completion of the 3 Na+/2 K+ transport cycle.
However, the back-step occurs readily during Na+/K+ transport when
external K+ ion binding and occlusion are delayed, and it occurs
more frequently when lowered extracellular pH raises the
probability of protonation of the externally accessible carboxylate
side chain. The proton route passes through the Na+-selective
binding site III and is distinct from the principal pathway
traversed by the majority of transported Na+ and K+ ions that
passes through binding site II. The inferred occurrence of Na+/K+
exchange and H+ import during the same conformational cycle of a
single molecule identifies the Na+/K+ pump as a hybrid transporter.
Whether Na+/K+ pump–mediated proton inflow may have any
physiological or pathophysiological significance remains to be
clarified.

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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