4.5 Article

A2A R mediated modulation in IP3 levels altering the [Ca2+]i through cAMP-dependent PKA signalling pathway

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ELSEVIER
DOI: 10.1016/j.bbagen.2022.130242

Keywords

Adenosine A(2A) R; Ca2+ signalling; IP3; cAMP; cAMP-dependent PKA; Forskolin; Neomycin

Funding

  1. University Grant Commission (UGC), New Delhi, India
  2. UGC
  3. DBT
  4. DST
  5. CSIR
  6. University of Delhi

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The study demonstrated that A(2A) receptors modulate IP3 levels to release cytoplasmic calcium via cAMP-dependent PKA, potentially opening new avenues in the therapy of neurodegenerative disorders.
Stimulation of A(2A) receptors (A(2A) R) coupled to G(s)/olf protein activates Adenylyl cyclase (AC) leading to the release of cAMP which activates the cAMP-dependent PKA phosphorylation. The possible role of A(2A) R in the modulation of free cytosolic Ca2+ concentration ([Ca2+](i)) involving IP3, cAMP and PKA was investigated in HEK 293-A(2A) R. The levels of IP3 and cAMP were observed by enzyme immunoassay detection method and [Ca2+](i) using Fluo-4 AM. Moreover, cAMP-dependent PKA was determined using the PKA Colorimetric Activity Kit. We observed that the cells pre-treated with A(2A) R agonist NECA showed increased levels of cAMP, PKA, IP3 and [Ca2+](i) levels. However, the reverse effect was observed with A(2A) R antagonists (ZM241385 and caffeine). Blocking the G(alpha q)/PLC/DAG/IP3 pathway with neomycin, a PLC inhibitor did not affect the modulation of IP3 and [Ca2+](i) levels in HEK 293-A(2A) R cells. To investigate the G(alpha i)/AC/cAMP/PKA, HEK 293-A(2A) R cells pre-treated with pertussis toxin followed by forskolin in the presence of A(2A) R agonist (NECA) showed no effect on cAMP levels. Further, G(alpha s)/AC/cAMP/PKA pathway was investigated to elucidate the role of cAMP-dependent PKA in IP3 mediated [Ca2+](i) modulation. In the HEK 293-A(2A) R cells pre-treated with PKA inhibitor KT5720 and treated with NECA led to inhibit the IP3 and [Ca2+](i) levels. The study distinctly demonstrated that A(2A) R modulates IP3 levels to release the [Ca2+](i) via cAMP-dependent PKA. The role of A(2A) R mediated G(alpha s) pathway inducing IP3 mediated [Ca2+](i) release may open new avenues in the therapy of neurodegenerative disorder.

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