Adrenergic receptor activation involves ATP release and feedback through purinergic receptors.
Formyl peptide receptor-induced chemotaxis of neutrophils depends on the release of ATP and autocrine feedback through purinergic receptors. Here, we show that adrenergic receptor signaling requires similar purinergic feedback mechanisms. Real-time RT-PCR analysis revealed that human embryonic kidney (HEK)-293 cells express several subtypes of adrenergic (α(1)-, α(2)-, and β-receptors), adenosine (P1), and nucleotide receptors (P2). Stimulation of G(q)-coupled α(1)-receptors caused release of cellular ATP and MAPK activation, which was blocked by inhibiting P2 receptors with suramin. Stimulation of G(i)-coupled α(2)-receptors induced weak ATP release, while G(s)-coupled β-receptors caused accumulation of extracellular ADP and adenosine. β-Receptors triggered intracellular cAMP signaling, which was blocked by scavenging extracellular adenosine with adenosine deaminase or by inhibiting A2a adenosine receptors with SCH58261. These findings suggest that adrenergic receptors require purinergic receptors to elicit downstream signaling responses in HEK-293 cells. We evaluated the physiological relevance of these findings using mouse aorta tissue rings. Stimulation of α(1)-receptors induced ATP release and tissue contraction, which was reduced by removing extracellular ATP with apyrase or in the absence of P2Y(2) receptors in aorta rings from P2Y(2) receptor knockout mice. We conclude that, like formyl peptide receptors, adrenergic receptors require purinergic feedback mechanisms to control complex physiological processes such as smooth muscle contraction and regulation of vascular tone.
Sumi
Yuka
Y
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Woehrle
Tobias
T
Chen
Yu
Y
Yao
Yongli
Y
Li
Andrew
A
Junger
Wolfgang G
WG
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000033:anatomy & histology / Q000378:metabolism; D002460:Cell Line; D017630:Connexins / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011941:Receptors, Adrenergic / Q000235:genetics / Q000378:metabolism*; D011983:Receptors, Purinergic / Q000235:genetics / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D017630:Connexins; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D020033:Protein Isoforms; D011941:Receptors, Adrenergic; D011983:Receptors, Purinergic; D058473:Receptors, Purinergic P2Y2; D000255:Adenosine Triphosphate; D020928:Mitogen-Activated Protein Kinases