1. Intracellular cAMP signaling by soluble adenylyl cyclase
Martin Tresguerres, Lonny R. Levin, Jochen Buck 
Kidney International 
Volume 79, Issue 12, Pages (June 2011)
DOI: /ki
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2. Figure 1
Activation of soluble adenylyl cyclase (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 through membrane-transporting proteins (purple icon) such as anion exchangers, Na+/HCO3− cotransporters (NBCs), or cystic fibrosis transmembrane conductance regulators. sAC can also be activated by (D) Ca2+ entering the cell through membrane transporters (turquoise icon) such as voltage-dependent Ca2+ channels or potentially by Ca2+ release from the endoplasmic reticulum 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 through CA. See text for details. ATP, adenosine 5′ triphosphate; cAMP, cyclic adenosine 3′,5′ monophosphate.
Kidney International  , DOI: ( /ki )
Copyright © 2011 International Society of Nephrology Terms and Conditions

3. Figure 2
Intracellular cyclic adenosine 3′,5′ monophosphate (cAMP) signaling microdomains. cAMP signaling occurs in discrete intracellular compartments such as the membrane vicinity, focal points throughout the cytoplasm, 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.
Kidney International  , DOI: ( /ki )
Copyright © 2011 International Society of Nephrology Terms and Conditions

4. Figure 3
Regulation of V-type H+-ATPase (VHA) translocation by soluble adenylyl cyclase (sAC) and AMP-activated kinase (AMPK). (1) Extracellular HCO3− enters the cell through transporter proteins (purple icon) or is dehydrated into CO2, a reaction catalyzed by an extracellular carbonic anhydrase (CA). CO2 would then diffuse into the cell, where it is hydrated into H+ and HCO3− by an intracellular CA. (2) The elevated intracellular [HCO3−] activates sAC (3) to produce cAMP, which promotes (through 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) by 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.
Kidney International  , DOI: ( /ki )
Copyright © 2011 International Society of Nephrology Terms and Conditions