We report the cloning and characterization of rat α10, a previously unidentified member nicotinic acetylcholine receptor (nAChR) subunit gene family. The protein encoded by α10 nAChR is most similar to α9 nAChR, both genes are transcribed in adult mechanosensory hair cells. Injection Xenopus laevis oocytes with cRNA alone or pairwise combinations either α2-α6 β2-β4 cRNAs yielded no detectable ACh-gated currents. However, coinjection resulted appearance an unusual subtype. Compared homomeric...

The isk gene is expressed in many tissues. Pharmacological evidence from the inner ear suggests that mediates potassium secretion into endolymph. To examine consequences of IsK null mutation on function, and to produce a system useful for examining role(s) plays elsewhere, we have produced mouse strain carries disrupted locus. Knockout mice exhibit classic shaker/waltzer behavior. Hair cells degenerate, but those different organs degenerate at times. Functionally, show lacking isk, strial...

Patterned spontaneous activity is a hallmark of developing sensory systems. In the auditory system, rhythmic bursts are generated in cochlear hair cells and propagated along central pathways. The role these patterns development circuits has remained speculative. Here we demonstrate that blocking efferent cholinergic neurotransmission to mice lack α9 subunit nicotinic acetylcholine receptors (α9 KO mice) altered temporal fine structure without changing levels. showed severe impairment...

Cochlear outer hair cells (OHCs) express α9 nACh receptors and are contacted by descending, predominately cholinergic, efferent fibers originating in the CNS. Mice carrying a null mutation for gene were produced to investigate its role(s) auditory processing development of cell innervation. In knockout mice, most OHCs innervated one large terminal instead multiple smaller terminals as wild types, suggesting role subunit mature synaptic connections. mice also failed show suppression cochlear...

Abstract We have produced a neurochemical map of the cell bodies origin cochlear efferent terminals in rat by combining glutamic acid decarboxylase (GAD), choline acetyltransferase (ChAT) or calcitonin gene‐related peptide (CGRP)immunocytochemistry with retrograde transport horseradish peroxidase. The location are general agreement medial and lateral systems described White Warr ( J. Comp. Neurol. 219:203–214, 1983) some minor modifications. system consists at least two pools chemically...

Significance This study addresses the need to phase out opioids as major analgesic drugs for moderate severe chronic pain. We establish that a highly selective and potent inhibitor of α9α10 nicotinic acetylcholine receptor (nAChR) subtype prevents expression chemotherapy-induced neuropathic Thus, antagonists nAChR are potential leads nonopioid drug development. The effects inhibitors receptor, together with genetic studies, suggest key role in an intercellular signaling network can be...

In the mature cochlea, inner hair cells (IHCs) transduce acoustic signals into receptor potentials, communicating to brain by synaptic contacts with afferent fibers. Before onset of hearing, a transient efferent innervation is found on IHCs, mediated nicotinic cholinergic that may contain both α9 and α10 subunits. Calcium influx through activates calcium-dependent (SK2-containing) potassium channels. This inhibitory synapse thought disappear after hearing [after postnatal day 12 (P12)]. We...

In the rat central nervous system, mRNA encoding N-methyl-D-aspartate receptor subunit R1 is most ubiquitously distributed among cloned mRNAs of this glutamate subtype. The very abundantly expressed and coexpression necessary for functional expression all other subunits. Therefore, likely to be an essential component known receptors in brain. By employing sequence specific polyclonal antibodies, we demonstrate that brain R1, as well recombinantly protein, has apparent molecular mass 116 kDa...

Several ganglionic nicotinic acetylcholine receptor (nAChR) types are abundantly expressed in nonneuronal locations, but their functions remain unknown. We found that keratinocyte α7 nAChR controls homeostasis and terminal differentiation of epidermal keratinocytes required for formation the skin barrier. The effects functional inactivation on cell cycle progression, differentiation, apoptosis were studied monolayers treated with α-bungarotoxin or antisense oligonucleotides Acra7 homozygous...

Programmed cell death regulates a number of biological phenomena, and the apoptotic signal must itself be tightly controlled to avoid inappropriate death. We established genetic screen search for molecules that inhibit from Fas receptor. Here we report isolation gene, LFG, protects cells uniquely but not mechanistically related tumor necrosis factor α signal. LFG is widely distributed, remarkably highly expressed in hippocampus. can bind receptor, does regulate expression or interfere with...

The retinoblastoma protein pRb is required for cell-cycle exit of embryonic mammalian hair cells but not their early differentiation. However, its role in postnatal unknown. To study the function mature animals, we created a new conditional mouse model, with Rb gene deleted primarily inner ear. Progeny survive up to 6 months. During development, −/− continue divide and can transduce mechanical stimuli. adult mice exhibit profound hearing loss due progressive degeneration organ Corti. We show...

The transduction of sound in the auditory periphery, cochlea, is inhibited by efferent cholinergic neurons projecting from brainstem and synapsing directly on mechanosensory hair cells. One fundamental question neuroscience what role(s) this feedback plays our ability to hear. In present study, we have engineered a genetically modified mouse model which magnitude duration effects are increased, assess consequences manipulation cochlear function. We generated Chrna9L9'T line knockin mice with...

Although homomeric channels assembled from the alpha9 nicotinic acetylcholine receptor (nAChR) subunit are functional in vitro, electrophysiological, anatomical, and molecular data suggest that native cholinergic olivocochlear function is mediated via heteromeric nAChRs composed of both alpha10 subunits. To gain insight into vivo, we examined olivo cochlear innervation null-mutant mice. Electrophysiological recordings postnatal (P) days P8-9 inner hair cells revealed ACh-gated currents...

Spontaneous electrical activity generated by developing sensory cells and neurons is crucial for the maturation of neural circuits. The full mammalian auditory inner hair (IHCs) depends on patterns spontaneous action potentials during a ‘critical period’ development. intrinsic spiking IHCs can be modulated inhibitory input from cholinergic efferent fibres descending brainstem, which transiently innervate immature IHCs. However, it remains unknown whether this transient to required their...

Epithelialization, a major component of wound healing, depends on keratinocyte adhesion and migration. Initiation migration relies upon the ability keratinocytes to free themselves from neighboring cells basement membrane. The local cytotransmitter acetylcholine (ACh) controls locomotion through different classes ACh receptors (AChR). In this study, we explored signaling pathways downstream α9 AChR subtype that had been shown control cell shape cytoplasm mobility. Inactivation by...

Outer hair cells in the mammalian cochlea receive a cholinergic efferent innervation that constitutes effector arm of sound-evoked negative feedback loop. The well-studied suppressive effects acetylcholine (ACh) release from terminals are mediated by α9/α10 ACh receptors and potently blocked strychnine. Here, we report novel, efferent-mediated enhancement cochlear neural responses otoacoustic emissions mice. In controls, slow response amplitude to supranormal levels appears after recovery...

Cochlear hair cells use SK2 currents to shape responses cholinergic efferent feedback from the brain. Using SK2−/− mice, we demonstrate that, in addition their previously defined role modulating cell membrane potentials, channels are necessary for long-term survival of olivocochlear fibers and synapses. Loss gene also results loss electrically driven effects vivo, down regulation ryanodine receptors involved calcium-induced calcium release, main inducer nAChR evoked activity. Generation...

Cells of the inner ear face constant metabolic and structural stress. Exposure to intense sound or certain drugs destroys cochlea hair cells, which in mammals do not regenerate. Thus, an endogenous stress response system may exist within protect it from everyday stressors. We recently described existence corticotropin-releasing factor (CRF) mouse cochlea. The CRF receptor type 1 (CRFR1) is considered primary canonical target signaling, systemically plays essential role coordinating body-wide...