New perspectives in signaling mediated by receptors coupled to stimulatory G protein: the emerging significance of cAMP efflux and extracellular cAMP-adenosine pathway

Abstract

G protein-coupled receptors (GPCRs) linked to stimulatory G (Gs) proteins (GsPCRs) mediate increases in intracellular cyclic AMP as consequence of activation of nine adenylyl cyclases , which differ considerably in their cellular distribution and activation mechanisms. Once produced, cyclic AMP may act via distinct intracellular signaling effectors such as protein kinase A and the exchange proteins activated by cAMP (Epacs). More recently, attention has been focused on the efflux of cAMP through a specific transport system named multidrug resistance proteins that belongs to the ATP-binding cassette transporter superfamily. Outside the cell, cAMP is metabolized into adenosine, which is able to activate four distinct subtypes of adenosine receptors, members of the GPCR family: A1, A2A, A2B, and A3. Taking into account that this phenomenon occurs in numerous cell types, as consequence of GsPCR activation and increment in intracellular cAMP levels, in this review, we will discuss the impact of cAMP efflux and the extracellular cAMP-adenosine pathway on the regulation of GsPCR-induced cell response.

Keywords: ABC transporters; G protein-coupled receptors; adenosine; adenosine receptors; cAMP efflux; cyclic AMP; ecto-5′-nucleotidase; ecto-phosphodiesterase.

FIGURE 1

Feedback mechanisms mediated by the extracellular cAMP–adenosine cascade. Activation of receptors coupled to Gs protein (GsPCR) leads to stimulation of adenylyl cyclase (AC) and increased generation of cAMP, which may elicit localized cellular response via activation of effectors such as PKA or Epac (A,B), which are organized in microdomains via anchoring proteins, such as AKAP. cAMP may be hydrolyzed by intracellular phosphodiesterases (PDEs) or may leave the cell via multidrug resistance proteins (MRPs). Outside the cell, ecto-PDE and ecto-5′nucleotidase sequentially convert cAMP to AMP and adenosine (ADO), which may activate Gs-coupled A_2A/A_2B (A) or Gi-coupled A₁/A₃ (B) receptors, increasing or attenuating cAMP production, respectively. In addition, activation of receptors coupled to Gi protein (GiPCR) results in inhibition of Gi-sensitive ACs reducing both generation and efflux of cAMP (C), with consequent loss of autocrine/paracrine feedback signaling of extracellular cAMP.