Differential occurrence of reluctant openings in G-protein-inhibited N- and P/Q-type calcium channels.

  • Colecraft H
  • Patil P
  • Yue D
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Abstract

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 betagamma 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 Ca(2+) entry during action potentials, with potentially important consequences for the timing and efficacy of synaptic transmission.

Author-supplied keywords

  • Action Potentials
  • Action Potentials: physiology
  • Calcium Channels, N-Type
  • Calcium Channels, N-Type: physiology
  • Calcium Channels, P-Type
  • Calcium Channels, P-Type: physiology
  • Calcium Channels, Q-Type
  • Calcium Channels, Q-Type: physiology
  • Cells, Cultured
  • Electrophysiology
  • GTP-Binding Proteins
  • GTP-Binding Proteins: pharmacology
  • Humans
  • Kidney
  • Kidney: cytology
  • Neurotransmitter Agents
  • Neurotransmitter Agents: secretion
  • Patch-Clamp Techniques
  • Receptors, Muscarinic
  • Receptors, Muscarinic: physiology
  • Synaptic Transmission
  • Synaptic Transmission: physiology

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Authors

  • H M Colecraft

  • P G Patil

  • D T Yue

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