Abstract
Transmission at the mouse neuromuscular junction normally relies on P/Q-type channels, but became jointly dependent on both N- and R-type Ca(2+) channels when the PQ-type channel alpha(1A) subunit was deleted. R-type channels lay close to Ca(2+) sensors for exocytosis and I(K(Ca)) channel activation, like the P/Q-type channels they replaced. In contrast, N-type channels were less well localized, but abundant enough to influence secretion strongly, particularly when action potentials were prolonged. Our data suggested that active zone structures may select among multiple Ca(2+) channels in the hierarchy P/Q >R >N. The alpha(1A)-/- neuromuscular junction displayed several other differences from wild-type: lowered quantal content but greater ability to withstand reductions in the Ca(2+)/Mg(2+) ratio, and little or no paired-pulse facilitation, the latter findings possibly reflecting compensatory mechanisms at individual release sites. Changes in presynaptic function were also associated with a significant reduction in the size of postsynaptic acetylcholine receptor clusters.
Highlights
The relationship between voltage-gated calcium channels and Ca2ϩ sensors for exocytosis lies at the heart of excitation– secretion coupling yet is incompletely understood
What would happen to neurotransmission if the Ca2ϩ channels that normally trigger vesicular fusion were removed? The dominant Ca2ϩ entry mechanism for synaptic communication at most synapses is the Ca2ϩ channel known as PQ-type [6,7,8,9]
What happens to synaptic transmission at the neuromuscular junction (NMJ) if PQ-type channels are deleted? Various outcomes are possible: (i) Neurotransmission might be greatly deranged because specific Ca2ϩ channels play a critical structural role in organizing the presynaptic release machinery [20, 28], or in correctly aligning presynaptic release sites and postsynaptic receptors [29, 30]. (ii) Neurotransmission might not change at all if other Ca2ϩ channel types substituted perfectly for PQ-type channels, a plausible outcome given the highly homologous structure of multiple Ca2ϩ channel types [31], which jointly support transmitter release at many CNS synapses [32,33,34,35]. (iii) In an intermediate outcome, basic features of neuromuscular transmission might be retained, but with significant changes in the relationship between Ca2ϩ entry and downstream responses such as transmission or short-term plasticity
Summary
The relationship between voltage-gated calcium channels and Ca2ϩ sensors for exocytosis lies at the heart of excitation– secretion coupling yet is incompletely understood. The neuromuscular junction (NMJ) is an interesting system for examining the impact of removing ␣1A, having been the focus of pioneering work on the quantal nature of transmission [16], the steep dependence of transmitter release on Ca2ϩ entry [17], the fine structure of the presynaptic terminal [18,19,20], and many other features of synapses [21, 22].
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