Publication Date: 2004.
In the mature cochlea, inner hair cells (IHCs) transduce acoustic signals into receptor potentials, communicating to the brain by synaptic contacts with afferent fibers. Before the onset of hearing, a transient efferent innervation is found on IHCs, mediated by a nicotinic cholinergic receptor that may contain both α9 and α10 subunits. Calcium influx through that receptor activates calcium-dependent (SK2-containing) potassium channels. This inhibitory synapse is thought to disappear after the onset of hearing [after postnatal day 12 (P12)]. We documented this developmental transition using whole-cell recordings from IHCs in apical turns of the rat organ of Corti. Acetylcholine elicited ionic currents in 88-100% of IHCs between P3 and P14, but in only 1 of 11 IHCs at P16-P22. Potassium depolarization of efferent terminals caused IPSCs in 67% of IHCs at P3, in 100% at P7-P9, in 93% at P10-P12, but in only 40% at P13-P14 and in none of the IHCs tested between P16 and P22. Earlier work had shown by in situ hybridization that α9 mRNA is expressed in adult IHCs but that α10 mRNA disappears after the onset of hearing. In the present study, antibodies to α10 and to the associated calcium-dependent (SK2) potassium channel showed a similar developmental loss. The correlated expression of these gene products with functional innervation suggests that Alpha10 and SK2, but not Alpha9, are regulated by synaptic activity. Furthermore, this developmental knock-out of α10, but not α9, supports the hypothesis that functional nicotinic acetylcholine receptors in hair cells are heteromers containing both these subunits.
Author affiliation: Katz, E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Author affiliation: Gómez-Casati, M.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Keywords: α9α10 nAChR; Ca2+-activated K+ channel; Cholinergic; Efferent innervation; IHC; Mammalian cochlea; Neonatal development; Transient synapse; acetylcholine; calcium; calcium activated potassium channel; messenger RNA; nicotine; nicotinic receptor; nicotinic receptor alpha10 subunit; nicotinic receptor alpha9 subunit; potassium; receptor subunit; unclassified drug; Alpha10 gene; Alpha9 gene; animal cell; animal tissue; article; auditory stimulation; calcium transport; cochlea; Corti organ; depolarization; efferent nerve; gene; hair cell; hearing; in situ hybridization; ion current; knockout gene; newborn; nonhuman; postnatal development; priority journal; protein expression; rat; receptor potential; sensory nerve; signal transduction; sk2 gene; synapse; synaptogenesis; Acetylcholine; Action Potentials; Age Factors; Animals; Cochlea; Gene Expression Regulation, Developmental; Hair Cells, Inner; Hearing; Patch-Clamp Techniques; Potassium; Potassium Channels, Calcium-Activated; Protein Subunits; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Small-Conductance Calcium-Activated Potassium Channels; Synaptic Transmission.
Repository: Biblioteca Digital (UBA-FCEN). Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales
Authors: Sales, Maria Elena
Publication Date: 2016.
BACKGROUND: It is actually known that acetylcholine works as a signaling molecule in non-neuronal cells and tissues, in addition to its neuronal function as neurotransmitter. It can act on two types of receptors nicotinic and muscarinic receptors (mAChRs). The latter belong to the G protein coupled receptor family and there are five subtypes genetically cloned. Their activation triggers classical and non-classical intracellular signals that could be linked to the proliferation of normal and/or transformed cells. The M3 subtype was identified in different types of tumors and its stimulation with agonists triggers cell proliferation, migration, invasion and metastasis. RESULTS: Our laboratory has extensively investigated the expression and function of mAChRs in breast tumors from animal and human origins. We found a profuse expression of mAChRs in breast tumors, but opposite to this, an absence of these receptors in normal breast cells and tissues. The stimulation of mAChRs with the cholinergic agonist carbachol for 20 h increased tumor cell death. Moreover, the combination of subthreshold concentrations of the agonist with paclitaxel potentiates cell death. The usage of low dose chemotherapy with short drug free intervals was named metronomic therapy and it has emerged as a novel regimen for cancer treatment with very low incidence of side effects. CONCLUSION: Our work and that of others indicate that mAChRs that are over-expressed in different types of tumor cells could be a useful target for metronomic therapy in cancer treatment.
Author affiliation: Sales, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas