Intracellular cAMP signaling by soluble adenylyl cyclase

Abstract

Soluble adenylyl cyclase (sAC) is a recently identified source of the ubiquitous second messenger cyclic adenosine 3',5' monophosphate (cAMP). sAC is distinct from the more widely studied source of cAMP, the transmembrane adenylyl cyclases (tmACs); its activity is uniquely regulated by bicarbonate anions, and it is distributed throughout the cytoplasm and in cellular organelles. Due to its unique localization and regulation, sAC has various functions in a variety of physiological systems that are distinct from tmACs. In this review, we detail the known functions of sAC, and we reassess commonly held views of cAMP signaling inside cells.

Figure 1

Activation of sAC by HCO₃⁻ and Ca²⁺. Cytosolic sAC can be activated by HCO₃⁻ derived from carbonic anhydrase (CA)-dependent hydration of (a) external and (b) metabolic CO₂; and/or (c) HCO₃⁻ that enters via membrane transporting proteins (purple icon) such as anion exchangers, Na⁺/HCO₃⁻ cotransporters (NBC) or CFTRs. sAC can also be activated by (d) Ca²⁺ entering the cell via membrane transporters (green icon) such as voltage-dependent Ca²⁺ channels or potentially via Ca²⁺ release from the ER or mitochondria (not depicted). (e) HCO₃⁻ and Ca²⁺ can potentially activate sAC in the nucleus. (f) sAC inside mitochondria has been shown to be activated by metabolically generated CO₂ via CA. See text for details.

Figure 2

Intracellular cAMP signaling microdomains. cAMP signaling occurs in discrete intracellular compartments such as the membrane vicinity, focal cytoplasm points, mitochondria and the nucleus. Each microdomain contains (1) a source of cAMP (soluble adenylyl cyclase -sAC- or transmembrane adenylyl cyclase -tmAC-); (2) phosphodiesterases (PDE) that act as barriers for cAMP diffusion; and (3) cAMP targets such as protein kinase A (PKA) or Exchange proteins activated by cAMP (EPAC) (not illustrated). tmAC cAMP signaling occurs in response to various extracellular ligands and it requires modulation by G-Protein coupled receptors and heterotrimeric G-protein. The most widely described tmAC-dependent microdomain occurs at the cell membrane, but additional intracellular tmAC-dependent microdomains occur in endosomes after internalization. sAC present throughout the cytoplasm and in organelles such as mitochondria, nucleus, mid-bodies and centrioles define other microdomains. Additional regulation might involve the movement of sAC between compartments. See text for details.

Figure 3

Regulation of V-type H⁺-ATPase translocation by sAC and AMPK. (1) Extracellular HCO₃⁻ enters the cell via transporter proteins (purple icon) or is dehydrated into CO₂, a reaction catalyzed by extracellular carbonic anhydrase (CA_IV). CO₂ would then diffuse into the cell, where it is hydrated into H⁺ and HCO₃⁻ by intracellular carbonic anhydrase (CA_II). (2) The elevated intracellular [HCO₃⁻] activates sAC (3) to produce cAMP, which promotes (via PKA) (4) the insertion of VHA-containing vesicles into the cell membrane. (5) Membrane inserted VHAs secrete H⁺, which counteract the original alkalosis. (6) cAMP is hydrolyzed by phosphodiesterase (PDE) into AMP, which can (7) via stimulation of AMPK, inhibit the PKA mediated effects. This hypothetical mechanism, involving sequential activation of PKA and AMPK, could serve as a self-regulating circuit.