Cyclic AMP mediates keratinocyte directional migration in an electric field

Area of Science:

• Dermatology and Cell Biology
• Wound Healing Mechanisms
• Cellular Electrotaxis

Background:

• Re-epithelialization is crucial for wound closure, driven by directional keratinocyte migration.
• Endogenous electric fields (EFs) at wounding sites may guide keratinocyte movement.
• Beta-adrenergic receptors (beta-ARs) are present in keratinocytes, but their function in epidermal healing is unclear.

Purpose of the Study:

• To investigate the role of beta2-adrenergic receptors (beta2-ARs) in keratinocyte galvanotaxis (directional migration in response to EF).
• To elucidate the signaling pathways, specifically cyclic AMP (cAMP) involvement, mediating beta-AR effects on keratinocyte migration.

Main Methods:

• Keratinocyte migration assays were performed under controlled electric fields (100 mV mm(-1)).
• Cells were treated with varying concentrations of beta-AR agonists and antagonists.
• The effects of cAMP modulation (using agonists, antagonists, and specific analogs) on migration speed and directionality were assessed.

Main Results:

• High beta-AR agonist concentrations inhibited both random and directional migration speed via a cAMP-independent pathway.
• Low beta-AR agonist concentrations (0.1 pM to 0.1 nM) did not affect migration speed but abolished directional response to EF ('blinding').
• This 'blinding' effect was mediated by beta2-ARs and dependent on increased intracellular cAMP levels, as confirmed by experiments with cAMP-modulating agents.

Conclusions:

• Beta-adrenergic signaling differentially regulates keratinocyte migration: speed (cAMP-independent) and galvanotaxis (cAMP-dependent).
• Cyclic AMP (cAMP) plays a critical role in mediating the inhibitory effect of beta-ARs on keratinocyte galvanotaxis.
• Beta-AR agonists and antagonists represent potential therapeutic tools for modulating re-epithelialization and wound healing.