Compartmentalization of bicarbonate‐sensitive adenylyl cyclase in distinct signaling microdomains

Abstract

Intracellular targets of the ubiquitous second messenger cAMP are located at great distances from the most widely studied source of cAMP, the G protein responsive transmembrane adenylyl cyclases. We previously identified an alternative source of cAMP in mammalian cells lacking transmembrane spanning domains, the "soluble" adenylyl cyclase (sAC). We now demonstrate that sAC is distributed in specific subcellular compartments: mitochondria, centrioles, mitotic spindles, mid-bodies, and nuclei, all of which contain cAMP targets. Distribution at these intracellular sites proves that adenylyl cyclases are in close proximity to all cAMP effectors, suggesting a model in which local concentrations of cAMP are regulated by individual adenylyl cyclases targeted to specific microdomains throughout the cell.

A soluble adenylyl cyclase from sea urchin spermatozoa

“…After its cloning [36], mammalian sAC has been found in different cell compartments such as the nucleus [37][38][39], mitochondria and in membrane microdomains, such as caveolae, and lipid rafts, which are also known as the low density-detergent insoluble membrane fraction (LD-DIM) (reviewed in [40]). It is now known that in both nuclei and mitochondria the main source of cAMP synthesis is from sAC.…”

cAMP controls oxygen metabolism in mammalian cells

“…cAMP, produced by the plasma membrane adenylyl cyclase in response to hormones and neurotransmitters [7] and by the bicarbonate-activated soluble adenylyl cyclase, localised to the nucleus, mitochondria and other intracellular structures [8], plays a central regulatory role in energy-supplying and energy-requiring processes. cAMP dependent protein kinase (PKA), which is present in different subcellular compartments, including mitochondria [9], activates the utilisation of glycogen and lipid energy stores as well as energy-requiring processes, like cell growth and development, neuronal activity, etc.…”

A Defined Subset of Adenylyl Cyclases Is Regulated by Bicarbonate Ion

“…Additionally, a cytosolic form of AC (soluble adenylyl cyclase; sAC) has been identified in mammals that was demonstrated to be molecularly and biochemically distinct from the tmACs (5). Although most abundantly expressed in testis, sAC is expressed ubiquitously (6,7) and is directly activated by bicarbonate ion in a pH independent manner (8).…”