Voltage-dependent inhibition of N- and P/Q-type calcium channels by G proteins is crucial for presynaptic inhibition of neurotransmitter release, and may contribute importantly to short-term synaptic plasticity. Such calcium-channel modulation could thereby impact significantly the neuro-computational repertoire of neural networks. The differential modulation of N and P/Q channels could even further enrich their impact upon synaptic tuning. Here, we performed in-depth comparison of the G-protein inhibition of recombinant N and P/Q channels, expressed in HEK 293 cells with the m2 muscarinic receptor. While both channel types display classic features of G-protein modulation (kinetic slowing of activation, prepulse facilitation, and voltage dependence of inhibition), we confirmed previously reported quantitative differences, with N channels displaying stronger inhibition and greater relief of inhibition by prepulses. A more fundamental, qualitative difference in the modulation of these two channels was revealed by a modified tail-activation paradigm, as well as by a novel “slope” analysis method comparing time courses of slow activation and prepulse facilitation. The stark contrast in modulatory behavior can be understood within the context of the “willing–reluctant” model, in which binding of G-protein βγ subunits to channels induces a reluctant mode of gating, where stronger depolarization is required for opening. Our experiments suggest that only N channels could be opened in the reluctant mode, at voltages normally spanned by neuronal action potentials. By contrast, P/Q channels appear to remain closed, especially over these physiological voltages. Further, the differential occurrence of reluctant openings is not explained by differences in the rate of G-protein unbinding from the two channels. These two scenarios predict very different effects of G-protein inhibition on the waveform of Ca2+ entry during action potentials, with potentially important consequences for the timing and efficacy of synaptic transmission.
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1 February 2000
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February 01 2000
Differential Occurrence of Reluctant Openings in G-Protein–Inhibited N- and P/Q-Type Calcium Channels
Henry M. Colecraft,
Henry M. Colecraft
aFrom the Program in Molecular and Cellular Systems Physiology, Departments of Biomedical Engineering and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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Parag G. Patil,
Parag G. Patil
aFrom the Program in Molecular and Cellular Systems Physiology, Departments of Biomedical Engineering and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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David T. Yue
David T. Yue
aFrom the Program in Molecular and Cellular Systems Physiology, Departments of Biomedical Engineering and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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Henry M. Colecraft
aFrom the Program in Molecular and Cellular Systems Physiology, Departments of Biomedical Engineering and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Parag G. Patil
aFrom the Program in Molecular and Cellular Systems Physiology, Departments of Biomedical Engineering and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
David T. Yue
aFrom the Program in Molecular and Cellular Systems Physiology, Departments of Biomedical Engineering and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Abbreviations used in this paper: CCh, carbachol; Gβγ, G-protein βγ subunits.
Received:
October 01 1999
Revision Requested:
January 11 2000
Accepted:
January 12 2000
Online ISSN: 1540-7748
Print ISSN: 0022-1295
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
J Gen Physiol (2000) 115 (2): 175–192.
Article history
Received:
October 01 1999
Revision Requested:
January 11 2000
Accepted:
January 12 2000
Citation
Henry M. Colecraft, Parag G. Patil, David T. Yue; Differential Occurrence of Reluctant Openings in G-Protein–Inhibited N- and P/Q-Type Calcium Channels. J Gen Physiol 1 February 2000; 115 (2): 175–192. doi: https://doi.org/10.1085/jgp.115.2.175
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