Regulation by Ca2+-signaling pathways of adenylyl cyclases

Abstract

Interplay between the signaling pathways of the intracellular second messengers, cAMP and Ca(2+), has vital consequences for numerous essential physiological processes. Although cAMP can impact on Ca(2+)-homeostasis at many levels, Ca(2+) either directly, or indirectly (via calmodulin [CaM], CaM-binding proteins, protein kinase C [PKC] or Gβγ subunits) may also regulate cAMP synthesis. Here, we have evaluated the evidence for regulation of adenylyl cyclases (ACs) by Ca(2+)-signaling pathways, with an emphasis on verification of this regulation in a physiological context. The effects of compartmentalization and protein signaling complexes on the regulation of AC activity by Ca(2+)-signaling pathways are also addressed. Major gaps are apparent in the interactions that have been assumed, revealing a need to comprehensively clarify the effects of Ca(2+) signaling on individual ACs, so that the important ramifications of this critical interplay between Ca(2+) and cAMP are fully appreciated.

Figure 1.

General structural domains of the nine membrane-bound ACs. Each of the nine membrane-bound ACs consist of two transmembrane clusters (TM1 and TM2) each consisting of six membrane-spanning domains. TM1 and TM2 are joined by an intracellular loop containing the C1a and C1b regions. Following TM2 is a long intracellular tail, containing the C2a and C2b regions before the carboxyl terminus.

Figure 2.

Phylogenetic tree of the nine membrane-bound ACs. The sequences of the nine membrane-bound ACs, from five species (human, rat, mouse, dog, and cow) were analyzed for relatedness and a phylogenetic tree was constructed using the Phylogeny.fr server (Castresana 2000; Guindon and Gascuel 2003; Edgar 2004; Anisimova and Gascuel 2006; Chevenet et al. 2006; Dereeper et al. 2008). The branch length is proportional to the number of substitutions per site.

Figure 3.

Regulation of ACs by Ca²⁺. Ca²⁺ can directly, and indirectly regulate the nine membrane-bound ACs. Submicromolar [Ca²⁺] can directly regulate AC, and some ACs specifically respond to Ca²⁺ derived from capacitative Ca²⁺ entry (CCE) from store-operated Ca²⁺ channels (SOCCs). Ca²⁺ can also regulate AC by binding calmodulin (CaM), and the Ca²⁺/CaM complex can then affect AC activity. Ca²⁺-bound CaM can also activate Ca²⁺/calmodulin-activated kinase (CaMK) and calcineurin (CaN), both of which may regulate AC. More indirectly, Gβγ subunits from Gα_q linked receptors can also regulate AC activity. In addition, Gα_q can activate phospholipase C (PLC), which converts phosphatidylinositol 4,5-bisphosphate (PIP₂) to diacylglycerol (DAG) and inositol trisphosphate (IP₃). DAG activates protein kinase C (PKC), which can also modulate the activity of AC; InsP₃ binds to and activates its receptors (InsP₃R) on the endoplasmic reticulum (ER), thereby releasing Ca²⁺ from the ER stores into the cytoplasm. This emptying of the ER Ca²⁺ stores triggers extracellular Ca²⁺ entry by SOCCs.