RESUMEN
Administration of cocaine and amphetamine increases cocaine- and amphetamine-regulated transcript (CART) expression in the rat striatum (Douglass et al., 1995). CART mRNA is highly expressed in different parts of the human and rat brain, including hippocampus (Douglass et al., 1995; Couceyro et al., 1997; Kuhar and Yoho, 1999; Hurd and Fagergren, 2000). The presence of CART peptide 55-102 immunoreactivity in dense core vesicles of axon terminals suggests that the peptide may be released and may act as a neuromodulator (Smith et al., 1997) to induce neurophysiological and behavioral effects. Little is known, however, about CART peptide-responsive cells, receptor(s), or intracellular signaling mechanisms that mediate CART peptide action. Here we show that CART peptide 55-102 inhibits voltage-dependent intracellular Ca(2+) signaling and attenuates cocaine enhancement of depolarization-induced Ca(2+) influx in rat hippocampal neurons. The inhibitory effect of CART peptide 55-102 on Ca(2+) signaling is likely mediated by an inhibition of L-type voltage-gated Ca(2+) channel activity via a G-protein-dependent pathway. These results indicate that voltage-gated Ca(2+) channels in hippocampal neurons are targets for CART peptide 55-102 and suggest that CART peptides may be important in physiology and behavior mediated by the hippocampus, such as certain forms of learning and memory.
Asunto(s)
Canales de Calcio/metabolismo , Señalización del Calcio/fisiología , Hipocampo/metabolismo , Neuronas/metabolismo , Fragmentos de Péptidos/metabolismo , Animales , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/metabolismo , Señalización del Calcio/efectos de los fármacos , Células Cultivadas , Cocaína/antagonistas & inhibidores , Cocaína/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Colorantes Fluorescentes , Proteínas de Unión al GTP/metabolismo , Hipocampo/citología , Hipocampo/efectos de los fármacos , Proteínas del Tejido Nervioso , Neuronas/citología , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Fragmentos de Péptidos/farmacología , Potasio/farmacología , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Reactive oxygen species (ROS) and nitric oxide (NO) are important participants in signal transduction that could provide the cellular basis for activity-dependent regulation of neuronal excitability. In young rat cortical brain slices and undifferentiated PC12 cells, paired application of depolarization/agonist stimulation and oxidation induces long-lasting potentiation of subsequent Ca(2+) signaling that is reversed by hypoxia. This potentiation critically depends on NO production and involves cellular ROS utilization. The ability to develop the Ca(2+) signal potentiation is regulated by the developmental stage of nerve tissue, decreasing markedly in adult rat cortical neurons and differentiated PC12 cells.