Variability in P2X Receptor Composition in Human Taste Nerves: Implications for Treatment of Chronic Cough

Abstract

Antagonists to the P2X purinergic receptors on airway sensory nerves relieve refractory and unexplained chronic cough but can evoke unwanted dysgeusias because the gustatory nerves innervating taste buds express this same family of receptors. The subunit composition of the P2X receptors in these systems may, however, differ with implications for pharmacological intervention. In most species, the extrapulmonary airway nerves involved in cough predominantly express P2×3 subunits which form homotrimeric P2X3 receptors. In contrast, most sensory nerves innervating taste buds in mice express both P2X2 and P2X3 subunits, so the majority of receptors in that system are likely P2X2/P2X3 heteromers. Since neural P2X subunit composition can differ across species, we used immunohistochemistry to test whether taste nerves in humans and Rhesus monkeys express both P2X2 and P2X3 as in mice. In taste bud samples of fungiform papillae and larynx from humans and monkeys, all taste bud samples exhibit P2X3+ nerve fibers, but the majority lack substantial P2X2+. Of the 35 human subjects, only four (1 laryngeal, 3 fungiform) showed heavy P2X2 expression in taste nerves; none of the Rhesus samples showed P2X2. These findings suggest that for most humans, unlike mice, taste buds are innervated by nerve fibers predominantly expressing only P2X3 homomeric receptors and not P2X2/P2X3 heteromers. Thus, antagonists specific for P2X3 homomeric receptors might not be spared from affecting taste function in treated patients.