Graduate School of Medical Sciences
A partnership with the Sloan Kettering Institute

Lonny Levin

Our laboratory focuses on the second messenger molecule cAMP, which modulates cell growth and differentiation throughout evolution. Specifically, we study cAMP signaling originating from the bicarbonate-regulated Soluble Adenylyl Cyclase (sAC).


Our lab focuses on the second messenger cAMP. In eukaryotic cells, second messengers, such as cAMP, can play multiple, disparate roles within a single cell. This is achieved by compartmentalization into independently regulated signaling microdomains distributed throughout the cell. Each microdomain contains its own adenylyl cyclase to generate cAMP, effector protein for cAMP signal transduction and phosphodiesterase to degrade cAMP. Mammals possess two distinct classes of adenylyl cyclase, the hormone-responsive, transmembrane adenylyl cyclases (tmAC) and the bicarbonate-regulated soluble adenylyl cyclase (sAC). sAC has been shown to be the source of cAMP inside the mitochondrial matrix and inside the nucleus. (See Figure) 

We purified and cloned sAC, and it is now studied in our combined laboratory. Despite its more recent discovery, sAC represents the primordial cyclase in mammals. In contrast to tmACs, which are modulated by heterotrimeric G proteins in response to extracellular signals acting through seven-transmembrane spanning, G protein-coupled receptors, sAC is directly regulated by intracellular signals such as bicarbonate and calcium ions. In biological systems, carbonic anhydrases (CA) equilibrate bicarbonate ions with carbon dioxide and pH. Via this equilibrium, sAC and sAC-like cyclases, serve as “Natures carbon dioxide/bicarbonate/pH sensors” throughout evolution. 

sAC is most abundantly expressed in male germ cells, and it appears to mediate the bicarbonate-induced, cAMP-dependent processes required for sperm to fertilize an egg, including capacitation, hyperactivated motility, and the acrosome reaction. Being a bicarbonate/carbon dioxide chemosensor, sAC plays a number of other physiological roles in mammals. 

We are currently studying sAC-dependent physiologic processes using sAC knockout and inducible knockout mouse models, cell-lines, antibodies and multiple selective pharmacologic inhibitors developed in the lab. Current projects can be separated into to two broad categories: discovery of sAC physiologic functions and drug discovery efforts. 

Current Projects:

  • Developing sAC inhibitors into first of their kind on-demand contraceptives for men and women


For his PhD, at Cold Spring Harbor Laboratory, Dr. Levin studied the cAMP signaling pathway and regulation of Protein Kinase A (PKA). During his post-doctoral training, as a Howard Hughes Fellow at Johns Hopkins School of Medicine, he cloned and characterized the Rutabaga adenylyl cyclase integral for learning and memory formation in Drosophila melanogaster. He started as a faculty member at Weill Cornell Medicine in 1994, where he soon began his long-term collaboration with Dr. Jochen Buck.

Current Areas of Focus

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