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1.  Sodium entry during action potentials of mammalian central neurons: incomplete inactivation and reduced metabolic efficiency in fast-spiking neurons 
Neuron  2009;64(6):898-909.
We measured the time course of sodium entry during action potentials of mouse central neurons at 37 °C to examine how efficiently sodium entry is coupled to depolarization. In cortical pyramidal neurons, sodium entry was nearly completely confined to the rising phase of the spike: only ~25% more sodium enters than the theoretical minimum necessary for spike depolarization. However, in fast-spiking GABAergic neurons (cerebellar Purkinje cells and cortical interneurons), twice as much sodium enters as the theoretical minimum. The extra entry occurs because sodium channel inactivation is incomplete during the falling phase of the spike. The efficiency of sodium entry in different cell types is primarily a function of action potential shape and not cell type-specific differences in sodium channel kinetics. The narrow spikes of fast-spiking GABAergic neurons result in incomplete inactivation of sodium channels; this reduces metabolic efficiency but likely enhances the ability to fire spikes at high frequency.
PMCID: PMC2810867  PMID: 20064395
2.  Transient sodium current at subthreshold voltages: activation by EPSP waveforms 
Neuron  2012;75(6):1081-1093.
Tetrodotoxin (TTX)-sensitive sodium channels carry large transient currents during action potentials and also “persistent” sodium current, a non-inactivating TTX-sensitive current present at subthreshold voltages. We examined gating of subthreshold sodium current in dissociated cerebellar Purkinje neurons and hippocampal CA1 neurons, studied at 37 °C with near-physiological ionic conditions. Unexpectedly, in both cell types small voltage steps at subthreshold voltages activated a substantial component of transient sodium current as well as persistent current. Subthreshold EPSP-like waveforms also activated a large component of transient sodium current, but IPSP-like waveforms engaged primarily persistent sodium current with only a small additional transient component. Activation of transient as well as persistent sodium current at subthreshold voltages produces amplification of EPSPs that is sensitive to the rate of depolarization and can help account for the dependence of spike threshold on depolarization rate, as previously observed in vivo.
PMCID: PMC3460524  PMID: 22998875
CA1 pyramidal neuron; Purkinje neuron; persistent sodium current; IPSP; sodium channel
3.  Cleavage of TRPM7 releases the kinase domain from the ion channel and regulates its participation in Fas-induced apoptosis 
Developmental cell  2012;22(6):1149-1162.
Transient Receptor Potential Melastatin-like 7 (TRPM7) is a channel protein that also contains a regulatory serine-threonine kinase domain. Here, we find that Trpm7−/− T-cells are deficient in Fas-receptor induced apoptosis; TRPM7 channel activity participates in the apoptotic process and is regulated by caspase-dependent cleavage. This function of TRPM7 is dependent on its function as a channel, but not as a kinase. TRPM7 is cleaved by caspases at D1510, disassociating the carboxy-terminal kinase domain from the pore without disrupting the phosphotransferase activity of the released kinase, but substantially increasing TRPM7 ion channel activity. Furthermore, we show that TRPM7 regulates endocytic compartmentalization of the Fas receptor following receptor stimulation, an important process for apoptotic signaling through Fas receptors. These findings raise the possibility that other members of the TRP channel superfamily are also regulated by caspase-mediated cleavage with wide-ranging implications for cell death and differentiation.
PMCID: PMC3397829  PMID: 22698280

Results 1-3 (3)