RESUMO
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability, pacemaking, dendritic integration, and homeostatic plasticity and are culprits in aberrant neuronal activity in certain epilepsies. In this issue of Neuron two manuscripts (Santoro et al. and Zolles et al.) report that HCN channel gating and expression are controlled by Trip8b (Pex5R) but with a bidirectional spin.
Assuntos
Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Proteínas de Membrana/metabolismo , Canais de Potássio/metabolismo , Animais , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Ativação do Canal Iônico/fisiologia , Proteínas de Membrana/genética , Peroxinas , Canais de Potássio/genéticaRESUMO
The translocation of extracellular calcium (Ca(2+)) via voltage-gated Ca(2+) channels (VGCCs) in neurons is involved in triggering multiple physiological cell functions but also the abnormal, pathophysiological responses that develop as a consequence of injury. In conditions of neuropathic pain, VGCCs are involved in supplying the signal Ca(2+) important for the sustained neuronal firing and neurotransmitter release characteristic of these syndromes. Preclinical data have identified N-type VGCCs (Ca(v)2.2) as key participants in contributing to these Ca(2+) signaling events and clinical data with the peptide blocker Prialt have now validated Ca(v)2.2 as a bona fide target for future drug discovery efforts to identify new and novel therapeutics for neuropathic pain. Imperative for the success of such an endeavor will be the ability to identify compounds selective for Ca(v)2.2, versus other VGCCs, but also compounds which demonstrate effective blockade during the pathophysiological states of neuropathic pain without compromising channel activity associated with sustaining normal housekeeping cellular functions. An approach to obtain this research target profile is to identify compounds, which are more potent in blocking Ca(v)2.2 during higher frequencies of firing as compared to the slower more physiologically-relevant frequencies. This may be achieved by identifying compounds with enhanced potency for the inactivated state of Ca(v)2.2. This commentary explores the rationale and options for engineering a use-dependent blocker of Ca(v)2.2. It is anticipated that this use-dependent profile of channel blockade will result in new chemical entities with an improved therapeutic ratio for neuropathic pain.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo L/efeitos dos fármacos , Ativação do Canal Iônico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo N , Humanos , Conformação ProteicaRESUMO
Alternative splicing is a critical mechanism used extensively in the mammalian nervous system to increase the level of diversity that can be achieved by a set of genes. This review focuses on recent studies of voltage-gated calcium (Ca) channel Ca(v)alpha1 subunit splice isoforms in neurons. Voltage-gated Ca channels couple changes in neuronal activity to rapid changes in intracellular Ca levels that in turn regulate an astounding range of cellular processes. Only ten genes have been identified that encode Ca(v)alpha1 subunits, an insufficient number to account for the level of functional diversity among voltage-gated Ca channels. The consequences of regulated alternative splicing among the genes that comprise voltage-gated Ca channels permits specialization of channel function, optimizing Ca signaling in different regions of the brain and in different cellular compartments. Although the full extent of alternative splicing is not yet known for any of the major subtypes of voltage-gated Ca channels, it is already clear that it adds a rich layer of structural and functional diversity".
