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

Godinho RO, Duarte T, Pacini ES - Front Pharmacol (2015)

Bottom Line: Once produced, cyclic AMP may act via distinct intracellular signaling effectors such as protein kinase A and the exchange proteins activated by cAMP (Epacs).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.

View Article: PubMed Central - PubMed

Affiliation: Disciplina Farmacologia Celular, Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de SĂŁo Paulo SĂŁo Paulo, Brazil.

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.

No MeSH data available.


Related in: MedlinePlus

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 A2A/A2B(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.
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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 A2A/A2B(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.

Mentions: AR subtypes exhibit different affinities for the endogenous agonist (Muller and Jacobson, 2011): A1, A2A, and A3 display high to moderate affinity (Ki = 100, 310, and 290 nM, respectively) to adenosine whereas A2B has low affinity (Ki = 15 ÎĽM). Furthermore, distinct signaling transduction pathways are mobilized by each AR, leading to diverse cellular effects. The A1 and A3 are preferentially coupled to the Gi/o family of G-proteins whereas the A2A and A2B couple to Gs proteins (Trincavelli et al., 2010). Thus, as shown in Figure 1, depending on the receptor subtypes expressed in the cell, the extracellular cAMP-adenosine pathway will be able to increase (Figure 1A) or attenuate (Figure 1B) the intracellular cAMP production, by activating or inhibiting ACs, via Gs and Gi proteins, respectively. Therefore, the final biological effect of the extracellular cAMP-adenosine pathway will depend on AR subtype expressed by the target cell and on the amount of cAMP pumped out of the cell.


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

Godinho RO, Duarte T, Pacini ES - Front Pharmacol (2015)

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 A2A/A2B(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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4373373&req=5

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 A2A/A2B(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.
Mentions: AR subtypes exhibit different affinities for the endogenous agonist (Muller and Jacobson, 2011): A1, A2A, and A3 display high to moderate affinity (Ki = 100, 310, and 290 nM, respectively) to adenosine whereas A2B has low affinity (Ki = 15 ÎĽM). Furthermore, distinct signaling transduction pathways are mobilized by each AR, leading to diverse cellular effects. The A1 and A3 are preferentially coupled to the Gi/o family of G-proteins whereas the A2A and A2B couple to Gs proteins (Trincavelli et al., 2010). Thus, as shown in Figure 1, depending on the receptor subtypes expressed in the cell, the extracellular cAMP-adenosine pathway will be able to increase (Figure 1A) or attenuate (Figure 1B) the intracellular cAMP production, by activating or inhibiting ACs, via Gs and Gi proteins, respectively. Therefore, the final biological effect of the extracellular cAMP-adenosine pathway will depend on AR subtype expressed by the target cell and on the amount of cAMP pumped out of the cell.

Bottom Line: Once produced, cyclic AMP may act via distinct intracellular signaling effectors such as protein kinase A and the exchange proteins activated by cAMP (Epacs).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.

View Article: PubMed Central - PubMed

Affiliation: Disciplina Farmacologia Celular, Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de SĂŁo Paulo SĂŁo Paulo, Brazil.

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.

No MeSH data available.


Related in: MedlinePlus