RESUMO
T-type Ca2+ channels (T channels) underlie rhythmic burst discharges during neuronal oscillations that are typical during sleep. However, the Ca2+-dependent effectors that are selectively regulated by T currents remain unknown. We found that, in dendrites of nucleus reticularis thalami (nRt), intracellular Ca2+ concentration increases were dominated by Ca2+ influx through T channels and shaped rhythmic bursting via competition between Ca2+-dependent small-conductance (SK)-type K+ channels and Ca2+ uptake pumps. Oscillatory bursting was initiated via selective activation of dendritically located SK2 channels, whereas Ca2+ sequestration by sarco/endoplasmic reticulum Ca2+-ATPases (SERCAs) and cumulative T channel inactivation dampened oscillations. Sk2-/- (also known as Kcnn2) mice lacked cellular oscillations, showed a greater than threefold reduction in low-frequency rhythms in the electroencephalogram of non-rapid-eye-movement sleep and had disrupted sleep. Thus, the interplay of T channels, SK2 channels and SERCAs in nRt dendrites comprises a specialized Ca2+ signaling triad to regulate oscillatory dynamics related to sleep.
Assuntos
Relógios Biológicos/fisiologia , Dendritos/fisiologia , Núcleos da Linha Média do Tálamo/citologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/fisiologia , Sono/fisiologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/fisiologia , Anestésicos Locais/farmacologia , Animais , Animais Recém-Nascidos , Apamina/farmacologia , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Dendritos/ultraestrutura , Estimulação Elétrica/métodos , Eletroencefalografia/métodos , Inibidores Enzimáticos/farmacologia , Feminino , Técnicas In Vitro , Indóis/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Potenciais da Membrana/efeitos da radiação , Mibefradil/farmacologia , Camundongos , Camundongos Knockout , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/efeitos da radiação , Técnicas de Patch-Clamp , Canais de Potássio Ativados por Cálcio de Condutância Baixa/deficiência , Tetrodotoxina/farmacologia , Caminhada/fisiologiaRESUMO
Among the major families of voltage-gated Ca(2+) channels, the low-voltage-activated channels formed by the Ca(v)3 subunits, referred to as T-type Ca(2+) channels, have recently gained increased interest in terms of the intracellular Ca(2+) signals generated upon their activation. Here, we provide an overview of recent reports documenting that T-type Ca(2+) channels act as an important Ca(2+) source in a wide range of neuronal cell types. The work is focused on T-type Ca(2+) channels in neurons, but refers to non-neuronal cells in cases where exemplary functions for Ca(2+) entering through T-type Ca(2+) channels have been described. Notably, Ca(2+) influx through T-type Ca(2+) channels is the predominant Ca(2+) source in several neuronal cell types and carries out specific signaling roles. We also emphasize that Ca(2+) signaling through T-type Ca(2+) channels occurs often in select subcellular compartments, is mediated through strategically co-localized targets, and is exploited for unique physiological functions.