Commentary: Nicotinic acetylcholine receptor α9 and α10 subunits are expressed in the brain of mice

Fil: Morley, Barbara J.. Boys Town National Research Hospita; Estados UnidosFil: Whiteaker, Paul. Barrow Neurological Institute; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentin

The nicotinic receptor of cochlear hair cells: A possible pharmacotherapeutic target?

Mechanosensory hair cells of the organ of Corti transmit information regarding sound to the central nervous system by way of peripheral afferent neurons. In return, the central nervous system provides feedback and modulates the afferent stream of information through efferent neurons. The medial olivocochlear efferent system makes direct synaptic contacts with outer hair cells and inhibits amplification brought about by the active mechanical process inherent to these cells. This feedback system offers the potential to improve the detection of signals in background noise, to selectively attend to particular signals, and to protect the periphery from damage caused by overly loud sounds. Acetylcholine released at the synapse between efferent terminals and outer hair cells activates a peculiar nicotinic cholinergic receptor subtype, the α9α10 receptor. At present no pharmacotherapeutic approaches have been designed that target this cholinergic receptor to treat pathologies of the auditory system. The potential use of α9α10 selective drugs in conditions such as noise-induced hearing loss, tinnitus and auditory processing disorders is discussed.Fil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaFil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Fuchs, Paul A.. The Johns Hopkins University School of Medicine; Estados Unido

Waterborne polysulfide dispersions for coatings application.

309 p.Novel synthesis approach of high solids content film forming waterborne poly(thioethers), based on initiator-free step-growth sonopolymerization combined with photopolymerization in aqueous dispersed media is reported. With this process, ultra-high molar mass chains up to 200 kDa, the highest reported so far for step grown poly(thioethers) The crystallization of as-synthesized poly(thioethers) was studied by implementing a self-nucleation (SN) procedure in this polymer type, which take the advantage of the presence of a previous crystalline state memory that persists the melting process to boosts the re-crystallization kinetics. Crystallization studies were also implemented in poly(thioethers) with various chemical structures. Finally, we report the synthesis of film forming poly(thioethers) containing newly synthesized biobased monomers

Activity of nAChRs containing α9 subunits modulates synapse stabilization via bidirectional signaling programs

Although the synaptogenic program for cholinergic synapses of the neuromuscular junction is well known, little is known of the identity or dynamic expression patterns of proteins involved in non-neuromuscular nicotinic synapse development. We have previously demonstrated abnormal presynaptic terminal morphology following loss of nicotinic acetylcholine receptor (nAChR) α9 subunit expression in adult cochleae. However, the molecular mechanisms underlying these changes have remained obscure. To better understand synapse formation and the role of cholinergic activity in the synaptogenesis of the inner ear, we exploit the nAChR α9 subunit null mouse. In this mouse, functional acetylcholine (ACh) neurotransmission to the hair cells is completely silenced. Results demonstrate a premature, effusive innervation to the synaptic pole of the outer hair cells in α9 null mice coinciding with delayed expression of cell adhesion proteins during the period of effusive contact. Collapse of the ectopic innervation coincides with an age-related hyperexpression pattern in the null mice. In addition, we document changes in expression of presynaptic vesicle recycling/trafficking machinery in the α9 null mice that suggests a bidirectional information flow between the target of the neural innervation (the hair cells) and the presynaptic terminal that is modified by hair cell nAChR activity. Loss of nAChR activity may alter transcriptional activity, as CREB binding protein expression is decreased coincident with the increased expression of N-Cadherin in the adult α9 null mice. Finally, by using mice expressing the nondesensitizing α9 L90T point mutant nAChR subunit, we show that increased nAChR activity drives synaptic hyperinnervation. © 2009 Wiley Periodicals, Inc.Fil: Murthy, Vidya. Tufts University School of Medicine; EslovaquiaFil: Taranda, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Tufts University School of Medicine; EslovaquiaFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaFil: Vetter, Douglas E.. Tufts University School of Medicine; Eslovaqui

Short-term plasticity and modulation of synaptic transmission at mammalian inhibitory cholinergic olivocochlear synapses

The organ of Corti, the mammalian sensory epithelium of the inner ear, has two types of mechanoreceptor cells, inner hair cells (IHCs) and outer hair cells (OHCs). In this sensory epithelium, vibrations produced by sound waves are transformed into electrical signals. When depolarized by incoming sounds, IHCs release glutamate and activate auditory nerve fibers innervating them and OHCs, by virtue of their electromotile property, increase the amplification and fine tuning of sound signals. The medial olivocochlear (MOC) system, an efferent feedback system, inhibits OHC activity and thereby reduces the sensitivity and sharp tuning of cochlear afferent fibers. During neonatal development, IHCs fire Ca2C action potentials which evoke glutamate release promoting activity in the immature auditory system in the absence of sensory stimuli. During this period, MOC fibers also innervate IHCs and are thought to modulate their firing rate. Both the MOC-OHC and the MOC-IHC synapses are cholinergic, fast and inhibitory and mediated by the a9a10 nicotinic cholinergic receptor (nAChR) coupled to the activation of calcium-activated potassium channels that hyperpolarize the hair cells. In this review we discuss the biophysical, functional and molecular data which demonstrate that at the synapses between MOC efferent fibers and cochlear hair cells, modulation of transmitter release as well as short term synaptic plasticity mechanisms, operating both at the presynaptic terminal and at the postsynaptic hair-cell, determine the efficacy of these synapses and shape the hair cell response pattern.Fil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentin

Alpha9 nicotinic acetylcholine receptors and the treatment of pain

Chronic pain is a vexing worldwide problem that causes substantial disability and consumes significant medical resources. Although there are numerous analgesic medications, these work through a small set of molecular mechanisms. Even when these medications are used in combination, substantial amounts of pain often remain. It is therefore highly desirable to develop treatments that work through distinct mechanisms of action. While agonists of nicotinic acetylcholine receptors (nAChRs) have been intensively studied, new data suggest a role for selective antagonists of nAChRs. α-Conotoxins are small peptides used offensively by carnivorous marine snails known as Conus. A subset of these peptides known as α-conotoxins RgIA and Vc1.1 produces both acute and long lasting analgesia. In addition, these peptides appear to accelerate the recovery of function after nerve injury, possibly through immune mediated mechanisms. Pharmacological analysis indicates that RgIA and Vc1.1 are selective antagonists of α9α10 nAChRs. A recent study also reported that these α9α10 antagonists are also potent GABA-B agonists. In the current study, we were unable to detect RgIA or Vc1.1 binding to or action on cloned GABA-B receptors expressed in HEK cells or Xenopus oocytes. We review the background, findings and implications of use of compounds that act on α9* nAChRs.11* indicates the possible presence of additional subunits.Fil: McIntosh, J. Michael. University of Utah; Estados UnidosFil: Absalom, Nathan. The University of Sydney; AustraliaFil: Chebib, Mary. The University of Sydney; AustraliaFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaFil: Vincler, Michelle. Wake Forest University Health Sciences; Estados Unido

The evolutionary tuning of hearing

After the transition to life on land, tympanic middle ears emerged separately in different groups of tetrapods, facilitating the efficient detection of airborne sounds and paving the way for high frequency sensitivity. The processes that brought about high-frequency hearing in mammals are tightly linked to the accumulation of coding sequence changes in inner ear genes; many of which were selected during evolution. These include proteins involved in hair bundle morphology, mechanotransduction and high endolymphatic potential, somatic electromotility for sound amplification, ribbon synapses for high-fidelity transmission of sound stimuli, and efferent synapses for the modulation of sound amplification. Here, we review the molecular evolutionary processes behind auditory functional innovation. Overall, the evidence to date supports the hypothesis that changes in inner ear proteins were central to the fine tuning of mammalian hearing

Tinnitus and Coxsackie B infections: A case series

Tinnitus is a frequent and often debilitating condition. There is consensus in the scientific community that there exist various forms of tinnitus, which differ in their pathogenesis. Here we report a series of five cases where the onset of tinnitus was associated with viral infections. In all five patients elevated antibodies against Coxsackie B have been detected. This observation suggests that Coxsackie B Virus infections might be involved in the development of some cases of tinnitus and indicate that further systematic investigations are warranted.Fil: Langguth, Berthold. Universitat Regensburg; AlemaniaFil: Stadtlaender, Hans. An der Zuckerfabrik 2; AlemaniaFil: Landgrebe, Michael. Universitat Regensburg; AlemaniaFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Coors, Hermann. Gaußstr 10; AlemaniaFil: Vielsmeier, Veronika. Universitat Regensburg; AlemaniaFil: Kleinjung, Tobias. Universitat Regensburg; Alemani

The Hair Cell α9α10 Nicotinic Acetylcholine Receptor: Odd Cousin in an Old Family

Nicotinic acetylcholine receptors (nAChRs) are a subfamily of pentameric ligand-gated ion channels with members identified in most eumetazoan clades. In vertebrates, they are divided into three subgroups, according to their main tissue of expression: neuronal, muscle and hair cell nAChRs. Each receptor subtype is composed of different subunits, encoded by paralogous genes. The latest to be identified are the α9 and α10 subunits, expressed in the mechanosensory hair cells of the inner ear and the lateral line, where they mediate efferent modulation. α9α10 nAChRs are the most divergent amongst all nicotinic receptors, showing marked differences in their degree of sequence conservation, their expression pattern, their subunit co-assembly rules and, most importantly, their functional properties. Here, we review recent advances in the understanding of the structure and evolution of nAChRs. We discuss the functional consequences of sequence divergence and conservation, with special emphasis on the hair cell α9α10 receptor, a seemingly distant cousin of neuronal and muscle nicotinic receptors. Finally, we highlight potential links between the evolution of the octavolateral system and the extreme divergence of vertebrate α9α10 receptors

Short-term synaptic plasticity regulates the level of olivocochlear inhibition to auditory hair cells

In the mammalian inner ear, the gain control of auditory inputs is exerted by medial olivocochlear (MOC) neurons that innervate cochlear outer hair cells (OHCs). OHCs mechanically amplify the incoming sound waves by virtue of their electromotile properties while the MOC system reduces the gain of auditory inputs by inhibiting OHC function. How this process is orchestrated at the synaptic level remains unknown. In the present study, MOC firing was evoked by electrical stimulation in an isolated mouse cochlear preparation, while OHCs postsynaptic responses were monitored by whole-cell recordings. These recordings confirmed that electrically evoked IPSCs (eIPSCs) are mediated solely by α9β10 nAChRs functionally coupled to calcium-activated SK2 channels. Synaptic release occurred with low probability when MOC-OHC synapses were stimulated at 1 Hz. However, as the stimulation frequency was raised, the reliability of release increased due to presynaptic facilitation. In addition, the relatively slow decay of eIPSCs gave rise to temporal summation at stimulation frequencies >10 Hz. The combined effect of facilitation and summation resulted in a frequency-dependent increase in the average amplitude of inhibitory currents in OHCs. Thus, we have demonstrated that short-term plasticity is responsible for shaping MOC inhibition and, therefore, encodes the transfer function from efferent firing frequency to the gain of the cochlear amplifier.Fil: Ballestero, Jimena Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Zorrilla de San Martín, Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Goutman, Juan Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Fuchs, Paul A.. The Johns Hopkins University School of Medicine; Estados UnidosFil: Katz, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentin