Ion Channels in Endothelial Responses to Fluid Shear Stress.

Fluid shear stress is an important environmental cue that governs vascular physiology and pathology, but the molecular mechanisms that mediate endothelial responses to flow are only partially understood. Gating of ion channels by flow is one mechanism that may underlie many of the known responses. Here, we review the literature on endothelial ion channels whose activity is modulated by flow with an eye toward identifying important questions for future research.

Comparative biology of decellularized lung matrix: Implications of species mismatch in regenerative medicine.

Lung engineering is a promising technology, relying on re-seeding of either human or xenographic decellularized matrices with patient-derived pulmonary cells. Little is known about the species-specificity of decellularization in various models of lung regeneration, or if species dependent cell-matrix interactions exist within these systems. Therefore decellularized scaffolds were produced from rat, pig, primate and human lungs, and assessed by measuring residual DNA, mechanical properties, and key matrix proteins (collagen, elastin, glycosaminoglycans). To study intrinsic matrix biologic cues, human endothelial cells were seeded onto acellular slices and analyzed for markers of cell health and inflammation. Despite similar levels of collagen after decellularization, human and primate lungs were stiffer, contained more elastin, and retained fewer glycosaminoglycans than pig or rat lung scaffolds. Human endothelial cells seeded onto human and primate lung tissue demonstrated less expression of vascular cell adhesion molecule and activation of nuclear factor-κB compared to those seeded onto rodent or porcine tissue. Adhesion of endothelial cells was markedly enhanced on human and primate tissues. Our work suggests that species-dependent biologic cues intrinsic to lung extracellular matrix could have profound effects on attempts at lung regeneration.

The star-nosed mole reveals clues to the molecular basis of mammalian touch.

Little is known about the molecular mechanisms underlying mammalian touch transduction. To identify novel candidate transducers, we examined the molecular and cellular basis of touch in one of the most sensitive tactile organs in the animal kingdom, the star of the star-nosed mole. Our findings demonstrate that the trigeminal ganglia innervating the star are enriched in tactile-sensitive neurons, resulting in a higher proportion of light touch fibers and lower proportion of nociceptors compared to the dorsal root ganglia innervating the rest of the body. We exploit this difference using transcriptome analysis of the star-nosed mole sensory ganglia to identify novel candidate mammalian touch and pain transducers. The most enriched candidates are also expressed in mouse somatosesensory ganglia, suggesting they may mediate transduction in diverse species and are not unique to moles. These findings highlight the utility of examining diverse and specialized species to address fundamental questions in mammalian biology.

TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch.

Itch, the unpleasant sensation that evokes a desire to scratch, accompanies numerous skin and nervous system disorders. In many cases, pathological itch is insensitive to antihistamine treatment. Recent studies have identified members of the Mas-related G protein-coupled receptor (Mrgpr) family that are activated by mast cell mediators and promote histamine-independent itch. MrgprA3 and MrgprC11 act as receptors for the pruritogens chloroquine and BAM8-22, respectively. However, the signaling pathways and transduction channels activated downstream of these pruritogens are largely unknown. We found that TRPA1 is the downstream target of both MrgprA3 and MrgprC11 in cultured sensory neurons and heterologous cells. TRPA1 is required for Mrgpr-mediated signaling, as sensory neurons from TRPA1-deficient mice exhibited markedly diminished responses to chloroquine and BAM8-22. Similarly, TRPA1-deficient mice displayed little to no scratching in response to these pruritogens. Our findings indicate that TRPA1 is an essential component of the signaling pathways that promote histamine-independent itch.

Molecular and cellular mechanisms of trigeminal chemosensation.

Three sensory systems, olfaction, taste, and somatosensation, are dedicated to the detection of chemicals in the environment. Trigeminal somatosensory neurons enable us to detect a wide range of environmental stimuli, including pressure, temperature, and chemical irritants, within the oral and nasal mucosa. Natural plant-derived irritants have served as powerful pharmacological tools for identifying receptors underlying somatosensation. This is illustrated by the use of capsaicin, menthol, and wasabi to identify the heat-sensitive ion channel TRPV1, the cold-sensitive ion channel TRPM8, and the irritant receptor TRPA1, respectively. In addition to TRP channels, members of the two-pore potassium channel family have also been implicated in trigeminal chemosensation. KCNK18 was recently identified as a target for hydroxy-alpha-sanshool, the tingling and numbing compound produced in Schezuan peppers and other members of the Xanthoxylum genus. The role of these channels in trigeminal thermosensation and pain will be discussed.