Angiotensin-II Type 1 and Type 2 Receptors Differentially Regulate TWIK1 Potassium Channel Expression in Wistar Rat Sensory Neurons

Abstract

Two-pore domain potassium (K2P) channels control resting membrane potential of neurons and contribute to pain hypersensitivity when their expression or function is reduced. Tandem of P-domains in a Weak Inwardly rectifying K⁺ channel 1 (TWIK1) is broadly expressed in the nervous system, yet little is known about its regulation in dorsal root ganglion (DRG) neurons. Because components of the renin–angiotensin system (RAS) modulate sensory excitability, we investigated whether Angiotensin-II (Ang II) and its receptors, AT1R and AT2R, regulate TWIK1 expression. Using primary DRG cultures, we found that Ang II significantly increased TWIK1 mRNA and protein at 1–2 days in vitro. Quantitative immunocytochemistry revealed receptor-specific effects: TWIK1 up-regulation at 1 day was primarily AT2R-dependent, whereas AT1R contributed to a lesser extent. TWIK1 expression declined by 2 days but remained sensitive to receptor blockade. To test physiological relevance, we injected Ang II intradermally into the hindpaw of adult rats. Repeated—but not single—Ang II injections produced a modest reduction of TWIK1 in large L5 DRG neurons and in NF200-positive cutaneous terminals. This decrease was accompanied by mild mechanical hypersensitivity without changes in cold sensitivity. These in vivo effects align with preferential AT1R expression in medium and large DRG neurons and with the in vitro finding that TWIK1 down-regulation is most evident when AT1R remains active. These results identify TWIK1 as a downstream target of Ang II signaling in sensory neurons and suggest that RAS-dependent modulation of K2P channels may influence neuronal excitability and contribute to pain-related processes.