Nicotinic Alpha9 and Alpha10 Subunits: Ancient Receptors in Modern Times and Modern Places

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Background

Nicotinic acetylcholine receptors (nAChRs) are ion-gated channels that have diverse function in nervous and non-nervous tissues. The α9 and α10 subunits are members of the subfamily I, epithelial ion-gated nicotinic receptor gene family. These subunits are the most recently discovered (and perhaps the last to be discovered) nAChR subunits in mammals, but are phylogenetically the oldest.

The α9 and α10 subunits are not expressed in the mammalian brain, making them unique among nAChRs. They were first localized in cochlear hair cells. As a consequence of their discovery in hair cells, the focus of study of these subunits has largely been on their function in the cochlea. They are localized at postsynaptic sites in hair cells, where they mediate the neurotransmitter actions of acetylcholine (ACh). They have important functions during development and in the protection of the ear from damaging noise. The physiology and pharmacology of the hair cell receptor is identical to that of the α9/10 receptor expressed in Xenopus oocytes. Positive Darwinian evolutionary changes in the mammalian α10 subunit resulted in increased calcium permeability and parallels the evolution of the anion chloride transporter SLC26A5 (prestin) and somatic electromotility in cochlear OHCs. The mammalian α10 subunit, unlike the avian α10 subunit, does not form homomers when expressed in oocytes.

There is an emerging literature that the distribution of the α9 and α10 subunits in peripheral tissues is widespread and non-synaptic, regulated in disease states, and may not always be assembled as heteromeric receptors. One or both subunits are expressed in most immune cells, dorsal root ganglion, keratinocytes, brain glioblastoma, colon, human breast cancer. Their expression levels may be prognostic in cancer and osteoporosis, and recent evidence suggests they may be involved in immune regulation. Importantly, they are potential targets for treatment of pain, cancer, and inflammatory diseases.

Despite the recent upsurge in research interest in these subunits, there is much unknown about their functions and the underlying molecular mechanisms. They are most similar to the α7* nAChR; α-bungarotoxin and strychnine are antagonists of α7* and α9* receptors and α7* and α9* highly permeable to calcium. Recent evidence suggests a functional interaction of the subunits and potentially a structural association.

This Research Topic presents the current state of basic research activities on the function of α9 and a10 receptors, ideas about their roles in basic biology, physiology and inflammation and animal models for analysis of functions, and human disease states. This Research Topic encourages critical reviews and commentary on therapeutic potential and clinical interest in addition to research papers.

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