Weill Medical College of Cornell University
Bicarbonate-activated adenylyl cyclase and aging.
Caloric restriction extends life-span in a wide variety of eukaryotic organisms from yeast to mammals.
Cellular responses to nutritional availability are mediated by the cAMP signaling pathway in bacteria,
cyanobacteria, and unicellular eukaryotes, and Dr. Guarente and co-workers demonstrated the
glucose-activated cAMP-dependent protein kinase (PKA) pathway is directly linked to aging in
Together with Dr. Lonny Levin, our laboratory recently revealed the existence of a novel cAMP
signaling cascade in mammals. In addition to the more widely studied source of cAMP, the
hormonally-responsive, G protein-regulated, transmembrane adenylyl cyclases (tmACs), we identified
a second cascade defined by an intracellular form of adenylyl cyclase, the soluble adenylyl cyclase
(sAC). sAC seems to be ubiquitously expressed and is targeted to distinct subcellular locations within
cells; i.e., nucleus, cytoskeleton, and mitochondria. sAC is not subject to regulation via G proteins, and
its catalytic regions are more similar to cyanobacterial adenylyl cyclase (AC) catalytic domains than to
other eukaryotic cyclases.
We recently demonstrated that, among mammalian cyclases, sAC is uniquely regulated by bicarbonate
ions. Bicarbonate regulation of cyclase activity is conserved in cyanobacterial ACs suggesting an
evolutionary conserved signaling pathway which senses bicarbonate. Intracellular carbonic anhydrases
are present in all living organisms and instantaneously equilibrate cellular carbon dioxide and
bicarbonate levels. Because energy metabolism (i.e., utilization of glucose and/or fatty acids to generate
ATP) produces carbon dioxide, bicarbonate regulation of sAC and cAMP levels could provide an
intrinsic mechanism for sensing the metabolic state of cells. While cellular responses to nutrient
availability have long been known to be under hormonal control (i.e., glucagon) via modulation of
tmACs and cAMP, we now propose that the cell also utilizes a signaling pathway originating from
sAC-generated cAMP to intrinsically monitor its nutritional state.
Proposed research: Using a combination of biochemical, cellular and transgenic approaches, we
propose to test the hypothesis that bicarbonate/carbon dioxide-regulated sAC acts as a nutritional
sensor to monitor the metabolic state of mammalian cells, and to examine whether sAC is directly
involved in aging via generation of the second messenger cAMP.