Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic Ca(V)2.1 Ca2+ channels

作者：Nanou Evanthia; Yan Jin; Whitehead Nicholas P; Kim Min Jeong; Froehner Stanley C; Scheuer Todd; Catterall William A^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(4): 1068-1073.

DOI：10.1073/pnas.1524650113

• calcium channels
• synaptic facilitation
• calcium sensor proteins
• calmodulin
• synaptic plasticity

Facilitation and inactivation of P/Q-type calcium (Ca2+) currents through the regulation of voltage-gated Ca2+ (Ca-V)2.1 channels by Ca2+ sensor (CaS) proteins contributes to the facilitation and rapid depression of synaptic transmission in cultured neurons that transiently express Ca(V)2.1 channels. To examine the modulation of endogenous Ca(V)2.1 channels by CaS proteins in native synapses, we introduced a mutation (IM-AA) into the CaS protein-binding site in the C-terminal domain of Ca(V)2.1 channels in mice, and tested synaptic facilitation and depression in neuromuscular junction synapses that use exclusively Ca(V)2.1 channels for Ca2+ entry that triggers synaptic transmission. Even though basal synaptic transmission was unaltered in the neuromuscular synapses in IM-AA mice, we found reduced short-term facilitation in response to paired stimuli at short interstimulus intervals in IM-AA synapses. In response to trains of action potentials, we found increased facilitation at lower frequencies (10-30 Hz) in IM-AA synapses accompanied by slowed synaptic depression, whereas synaptic facilitation was reduced at high stimulus frequencies (50-100 Hz) that would induce strong muscle contraction. As a consequence of altered regulation of Ca(V)2.1 channels, the hindlimb tibialis anterior muscle in IM-AA mice exhibited reduced peak force in response to 50 Hz stimulation and increased muscle fatigue. The IM-AA mice also had impaired motor control, exercise capacity, and grip strength. Taken together, our results indicate that regulation of Ca(V)2.1 channels by CaS proteins is essential for normal synaptic plasticity at the neuromuscular junction and for muscle strength, endurance, and motor coordination in mice in vivo.

• 出版日期2016-1-26