K2P channels and ultrasound neuromodulation: A mechanosensitive memory perspective

Recent work by Ben Abu and Wolfson introduces the concept of 'energetic memory' in ion channels, providing a mechanistic framework for ultrasound neuromodulation. This discussion examines how K2P (two-pore domain potassium) channels serve as primary mediators of mechanosensitive memory due to their small size (0.5 μm radius), constitutive activity, and critical physiological roles. In contrast, larger Kv channels (5 μm) show intermediate sensitivity while Na⁺ channels (50 μm) remain largely unaffected, creating size-dependent responses. Nanoindentor experiments demonstrate sustained membrane hyperpolarization following mechanical compression, validating the theoretical predictions. The energetic memory model explains ultrasound therapy's clinical efficacy through preferential K2P channel compression, energy system adaptation, and prolonged recovery phases. This framework enables rational optimization of therapeutic protocols and extends to other mechanically-based interventions, fundamentally expanding our understanding of neural plasticity beyond traditional electrical mechanisms.