Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential cation channel that is critical for transducing environmental irritant stimuli into nociceptor activity. Moreover, we find that pain and acute vascular reactions, including neurogenic inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers new insights into the pathogenesis of pain and neurovascular responses during bacterial infections and opens novel avenues for their treatment.

▪ Abstract The functional impact of ion channels in vascular endothelial cells (ECs) is still a matter of controversy. This review describes different types of ion channels in ECs and their role in electrogenesis, Ca²⁺ signaling, vessel permeability, cell-cell communication, mechano-sensor functions, and pH and volume regulation. One major function of ion channels in ECs is the control of Ca²⁺ influx either by a direct modulation of the Ca²⁺ influx pathway or by indirect modulation of K⁺ and Cl⁻ channels, thereby clamping the membrane at a sufficiently negative potential to provide the necessary driving force for a sustained Ca²⁺ influx. We discuss various mechanisms of Ca²⁺ influx stimulation: those that activate nonselective, Ca²⁺-permeable cation channels or those that activate Ca²⁺-selective channels, exclusively or partially operated by the filling state of intracellular Ca²⁺ stores. We also describe the role of various Ca²⁺- and shear stress-activated K⁺ channels and different types of Cl⁻ channels for the regulation of the membrane potential.