Our joint laboratory discovered a direct link between CO2/HCO3/pH and intracellular signaling pathways when we demonstrated soluble adenylyl cyclase (sAC) is an evolutionarily conserved bicarbonate sensor. Over the past decade, we have collaborated with a variety of laboratories to prove that sAC serves as a CO2/HCO3/pH chemosensor in mammalian sperm, epididymis, airway epithelia, glia, and inside the mitochondrial matrix. In the most recent funding period, we discovered that the sAC gene is alternatively spliced and uses multiple promoters to generate a variety of isoforms. We now propose to (A) identify which isoforms are expressed in individual CO2/HCO3/pH sensing tissues;(B) which CO2/HCO3/pH sensing functions are abrogated in a knockout mouse which removes a subset of these sAC isoforms;and (C) determine whether the newly identified sAC isoforms are also CO2/HCO3/pH sensors.

Public Health Relevance

CO2 and/or bicarbonate have been shown to modulate a number of physiological processes. We discovered the existence of a widely expressed signal transducing enzyme, sAC, which is directly modulated by bicarbonate ions. Because of the intimate relationship between bicarbonate, CO2 and pH, it is possible that some, if not all, of the CO2 dependent signaling processes are regulated by bicarbonate modulation of sAC and cAMP levels.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062328-12
Application #
8462627
Study Section
Special Emphasis Panel (ZRG1-DKUS-G (02))
Program Officer
Somers, Scott D
Project Start
2001-02-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
12
Fiscal Year
2013
Total Cost
$407,105
Indirect Cost
$164,419
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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