Jochen Buck   Professor of Pharmacology

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  • +1 212 746 6274

BICARBONATE-ACTIVATED SOLUBLE ADENYLYL CYCLASE

The second messenger molecule cAMP, which modulates cell growth and differentiation in organisms from bacteria to higher eukaryotes, is produced by adenylyl cyclases. Mammals possess two distinct classes of adenylyl cyclase, the hormone-responsive, transmembrane adenylyl cyclases (tmAC) and the bicarbonate-regulated Soluble Adenylyl Cyclase (sAC). sAC, which we purified and cloned in collaboration with Dr. Lonny Levin's Laboratory, and tmACs define distinct cAMP signaling pathways within eukaryotic cells. tmACs are modulated by heterotrimeric G proteins in response to extracellular signals acting through seven-transmembrane spanning, G protein-coupled receptors. In contrast, sAC is directly regulated by bicarbonate ions suggesting it functions as the physiological carbon dioxide chemosensor. sAC most closely resembles cyanobacterial adenylyl cyclases, and regulation by bicarbonate ions is also conserved in these cyclases from blue-green algae. Therefore, sAC may represent the primordial cyclase in mammals. 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. Additionally, as the only identified bicarbonate/carbon dioxide chemosensor in mammals, sAC may also be involved in fluid reabsorption in the kidney, fluid secretion in the ciliary bodies and choroid plexus, and metabolic regulation in response to nutritional signals. We are currently testing these hypothesized physiological functions by making inducible, tissue-specific knockouts of the sAC gene in mice. The evolutionary conservation from unicellular bacteria to man and its involvement in developmental changes spermatozoa undergo post-ejaculation suggest that sAC may be involved in sensing signals important to the cell as an individual entity instead of carrying out instructions originating in other parts of the organism. Additionally, the laboratory is studying enzymes involved in retinol (vitamin A) metabolism. Retinol is enzymatically processed to derivatives with distinct biological functions. For example, the vitamin A derivative anhydroretinol is found in high amounts in insect pupae, mammalian liver and lung and may be involved in the regulation of cell death. We purified and cloned retinol dehydratase, the enzyme producing anhydroretinol, and are studying its enzymatic mechanism. For further information see:

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Primary Email

  • jobuck@med.cornell.edu

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Primary Affiliation

  • Weill Cornell Medical College, Cornell University