Presynaptic G-protein-coupled receptors dynamically modify vesicle fusion, synaptic cleft glutamate concentrations, and motor behavior.

Understanding how neuromodulators regulate behavior requires investigating their effects on functional neural systems, but also their underlying cellular mechanisms. Utilizing extensively characterized lamprey motor circuits, and the unique access to reticulospinal presynaptic terminals in the intact spinal cord that initiate these behaviors, we investigated effects of presynaptic G-protein-coupled receptors on locomotion from the systems level, to the molecular control of vesicle fusion. 5-HT inhibits neurotransmitter release via a Gbetagamma interaction with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex that promotes kiss-and-run vesicle fusion.

Abnormal corticomotor excitability assessed in biceps brachii preceding pronator contraction post-stroke.

Objective: To assess corticomotor (CM) excitability of the antagonist biceps brachii (BB) post-stroke in preparation for pronator contraction. In healthy subjects, we previously demonstrated that prior to pronator contraction CM excitability of the antagonist BB was suppressed.

Methods: Transcranial magnetic stimulation (TMS) was used to assess pre-contraction changes in motor evoked potential (MEP) amplitude of the BB, when BB was acting either as an antagonist or an agonist.

Gbetagamma interferes with Ca2+-dependent binding of synaptotagmin to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex.

Presynaptic inhibitory G protein-coupled receptors (GPCRs) can decrease neurotransmission by inducing interaction of Gbetagamma with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. We have shown that this action of Gbetagamma requires the carboxyl terminus of the 25-kDa synaptosome-associated protein (SNAP25) and is downstream of the well known inhibition of Ca2+ entry through voltage-gated calcium channels. We propose a mechanism in which Gbetagamma and synaptotagmin compete for binding to the SNARE complex.

Suppression of motor evoked potentials in biceps brachii preceding pronator contraction.

Reciprocal control of antagonists is essential for coordinated limb movement. While Ia afferent dependent reciprocal inhibition has been extensively studied, reports of the control of antagonists during preparation for a motor action are limited. It has been demonstrated that corticomotor (CM) excitability of antagonists is suppressed prior to wrist extension/flexion suggesting the existence of a pre-contraction cortical control mechanism for distal upper limb antagonists.

Presynaptic G-protein-coupled receptors regulate synaptic cleft glutamate via transient vesicle fusion.

When synaptic vesicles fuse with the plasma membrane, they may completely collapse or fuse transiently. Transiently fusing vesicles remain structurally intact and therefore have been proposed to represent a form of rapid vesicle recycling. However, the impact of a transient synaptic vesicle fusion event on neurotransmitter release, and therefore on synaptic transmission, has yet to be determined.

Gbetagamma acts at the C terminus of SNAP-25 to mediate presynaptic inhibition.

Presynaptic inhibition mediated by G protein-coupled receptors may involve a direct interaction between G proteins and the vesicle fusion machinery. The molecular target of this pathway is unknown. We demonstrate that Gbetagamma-mediated presynaptic inhibition in lamprey central synapses occurs downstream from voltage-gated Ca(2+) channels.

5-HT prolongs ventral root bursting via presynaptic inhibition of synaptic activity during fictive locomotion in lamprey.

Locomotor pattern generation is maintained by integration of the intrinsic properties of spinal central pattern generator (CPG) neurons in conjunction with synaptic activity of the neural network. In the lamprey, the spinal locomotor CPG is modulated by 5-HT. On a cellular level, 5-HT presynaptically inhibits synaptic transmission and postsynaptically inhibits a Ca2+-activated K+ current responsible for the slow afterhyperpolarization (sAHP) that follows action potentials in ventral horn neurons.