Abstract
Neutrophil chemotaxis requires excitatory signals at the front and inhibitory signals at the back of cells, which regulate cell migration in a chemotactic gradient field. We have previously shown that ATP release via pannexin 1 (PANX1) channels and autocrine stimulation of P2Y2 receptors contribute to the excitatory signals at the front. Here we show that PANX1 also contributes to the inhibitory signals at the back, namely by providing the ligand for A2A adenosine receptors. In resting neutrophils, we found that A2A receptors are uniformly distributed across the cell surface. In polarized cells, A2A receptors redistributed to the back where their stimulation triggered intracellular cAMP accumulation and protein kinase A (PKA) activation, which blocked chemoattractant receptor signaling. Inhibition of PANX1 blocked A2A receptor stimulation and cAMP accumulation in response to formyl peptide receptor stimulation. Treatments that blocked endogenous A2A receptor signaling impaired the polarization and migration of neutrophils in a chemotactic gradient field and resulted in enhanced ERK and p38 MAPK signaling in response to formyl peptide receptor stimulation. These findings suggest that chemoattractant receptors require PANX1 to trigger excitatory and inhibitory signals that synergize to fine-tune chemotactic responses at the front and back of neutrophils. PANX1 channels thus link local excitatory signals to the global inhibitory signals that orchestrate chemotaxis of neutrophils in gradient fields.
Highlights
Chemotaxis requires excitatory and inhibitory signals at the front and back of cells
We have previously shown that ATP release via pannexin 1 (PANX1) channels and autocrine stimulation of P2Y2 receptors contribute to the excitatory signals at the front
In addition to such specific chemoattractant receptors, neutrophils depend on purinergic receptors that are activated by extracellular ATP and adenosine and play a central role in defining how cells respond to chemotactic agents [10]
Summary
Chemotaxis requires excitatory and inhibitory signals at the front and back of cells. Various local excitation and global inhibition (LEGI) models of chemotaxis were developed in attempts to explain how such excitatory and inhibitory feedback mechanisms might translate external chemotactic cues into the complex sequence of cellular events that regulate gradient sensing, polarization, and migration of neutrophils in a chemotactic gradient field [3,4,5,6]. These models are based on experimental evidence that has revealed that the excitatory mechanisms at the front involve molecules such as G␣i subunits of heterotrimeric G proteincoupled receptors (GPCRs), the small GTPases Rac and Cdc, as well as phosphoinositide 3-kinase (PI3K) (6 – 8). Our findings have revealed that A2A receptors are stimulated during chemotaxis, that they trigger cAMP and PKA signaling, and that autocrine A2A receptor activation provides global inhibition that offsets local excitatory signals at the front of polarized neutrophils
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