 |
The Journal of Neuroscience, March 30, 2005, 25(13):3341-3349; doi:10.1523/JNEUROSCI.0104-05.2005
 Previous Article | Next Article 
Cellular/Molecular
Molecular Determinants for Modulation of Persistent Sodium Current by G-Protein   Subunits
Massimo Mantegazza,1,2 *
Frank H. Yu,1 *
Andrew J. Powell,3
Jeffrey J. Clare,3
William A. Catterall,1 and
Todd Scheuer1
1Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington 98195-7280, 2Department of Neurophysiology, Istituto Neurologico Besta, 20126 Milan, Italy, and 3Department of Gene Expression and Protein Biochemistry, GlaxoSmithKline, Stevenage, Herts SG1 2NY, United Kingdom
Voltage-gated sodium channels are responsible for the upstroke of the action potential in most excitable cells, and their fast inactivation is essential for controlling electrical signaling. In addition, a noninactivating, persistent component of sodium current, INaP, has been implicated in integrative functions of neurons including threshold for firing, neuronal bursting, and signal integration. G-protein   subunits increase INaP, but the sodium channel subtypes that conduct INaP and the target site(s) on the sodium channel molecule required for modulation by G are poorly defined. Here, we show that INaP conducted by Nav1.1 and Nav1.2 channels (Nav1.1 > Nav1.2) is modulated by G; Nav1.4 and Nav1.5 channels produce smaller INaP that is not regulated by G. These qualitative differences in modulation by G are determined by the transmembrane body of the sodium channels rather than their cytoplasmic C-terminal domains, which have been implicated previously in modulation by G. However, the C-terminal domains determine the quantitative extent of modulation of Nav1.2 channels by G. Studies of chimeric and truncated Nav1.2 channels identify molecular determinants that affect modulation of INaP located between amino acid residue 1890 and the C terminus at residue 2005. The last 28 amino acid residues of the C terminus are sufficient to support modulation by G when attached to the proximal C-terminal domain. Our results further define the sodium channel subtypes that generate INaP and identify crucial molecular determinants in the C-terminal domain required for modulation by G when attached to the transmembrane body of a responsive sodium channel.
Key words: sodium; channels; G-proteins; inactivation; neuromodulation; excitability
Received Aug 16, 2004;
accepted January 27, 2005.
This article has been cited by other articles:
|
|
|
|
 
R. Rusconi, P. Scalmani, R. R. Cassulini, G. Giunti, A. Gambardella, S. Franceschetti, G. Annesi, E. Wanke, and M. Mantegazza
Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+ Channel Mutant
J. Neurosci.,
October 10, 2007;
27(41):
11037 - 11046.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Kalume, F. H. Yu, R. E. Westenbroek, T. Scheuer, and W. A. Catterall
Reduced Sodium Current in Purkinje Neurons from NaV1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy
J. Neurosci.,
October 10, 2007;
27(41):
11065 - 11074.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Chen, J. D. Bohanick, M. Nishihara, J. K. Seamans, and C. R. Yang
Dopamine D1/5 Receptor-Mediated Long-Term Potentiation of Intrinsic Excitability in Rat Prefrontal Cortical Neurons: Ca2+-Dependent Intracellular Signaling
J Neurophysiol,
March 1, 2007;
97(3):
2448 - 2464.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. A. Wooltorton, S. Gaboyard, K. M. Hurley, S. D. Price, J. L. Garcia, M. Zhong, A. Lysakowski, and R. A. Eatock
Developmental Changes in Two Voltage-Dependent Sodium Currents in Utricular Hair Cells
J Neurophysiol,
February 1, 2007;
97(2):
1684 - 1704.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Carlier, V. Sourdet, S. Boudkkazi, P. Deglise, N. Ankri, L. Fronzaroli-Molinieres, and D. Debanne
Metabotropic glutamate receptor subtype 1 regulates sodium currents in rat neocortical pyramidal neurons
J. Physiol.,
November 15, 2006;
577(1):
141 - 154.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Scalmani, R. Rusconi, E. Armatura, F. Zara, G. Avanzini, S. Franceschetti, and M. Mantegazza
Effects in Neocortical Neurons of Mutations of the Nav1.2 Na+ Channel causing Benign Familial Neonatal-Infantile Seizures
J. Neurosci.,
October 4, 2006;
26(40):
10100 - 10109.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. P. Abbracchio, G. Burnstock, J.-M. Boeynaems, E. A. Barnard, J. L. Boyer, C. Kennedy, G. E. Knight, M. Fumagalli, C. Gachet, K. A. Jacobson, et al.
International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy
Pharmacol. Rev.,
September 1, 2006;
58(3):
281 - 341.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Aracri, E. Colombo, M. Mantegazza, P. Scalmani, G. Curia, G. Avanzini, and S. Franceschetti
Layer-Specific Properties of the Persistent Sodium Current in Sensorimotor Cortex
J Neurophysiol,
June 1, 2006;
95(6):
3460 - 3468.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Astman, M. J. Gutnick, and I. A. Fleidervish
Persistent sodium current in layer 5 neocortical neurons is primarily generated in the proximal axon.
J. Neurosci.,
March 29, 2006;
26(13):
3465 - 3473.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Osorio, G. Alcaraz, F. Padilla, F. Couraud, P. Delmas, and M. Crest
Differential targeting and functional specialization of sodium channels in cultured cerebellar granule cells
J. Physiol.,
December 15, 2005;
569(3):
801 - 816.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mantegazza, A. Gambardella, R. Rusconi, E. Schiavon, F. Annesi, R. R. Cassulini, A. Labate, S. Carrideo, R. Chifari, M. P. Canevini, et al.
Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures
PNAS,
December 13, 2005;
102(50):
18177 - 18182.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
