Modulation of Presynaptic Calcium Channels

This book will bring together leading international experts to discuss recent advances in basic scientific knowledge regarding the regulation of presynaptic Ca2+ channels. Importantly, Ca2+ channels represent one of the most widely modulated proteins in the body, being the target of a range of effector pathways and drugs; this range will be fully represented here. A number of therapeutic drugs target the Ca2+ channel complex, including the anti-epileptic gabapentinoid and analgesic ziconotide drugs and the pharmaceutical industry is searching for Ca2+ channel blocking drugs, particularly in the pain, epilepsy, ataxia and migraine areas. Such potential future therapies will be discussed here. Scientific disciplines will focus on electrophysiological studies, but will extend to neuroscience, genetics and biochemical areas. The work described will represent advances at the cutting edge of current neuroscience research and is timely and highly appropriate for the Springer book series.

This book brings together leading international experts to discuss recent advances in the regulation of presynaptic voltage-gated Ca²⁺ channels (VGCCs), key signal transducers that represent one of the most widely modulated proteins in the body. It is now commonly accepted that presence of the VGCC complex defines an excitable cell. At a basic level, VGCCs transduce membrane potential change to chemical neurotransmitter release at presynaptic terminals. However, on-going scientific research, presented here, in areas including neuroscience, electrophysiology, pharmacology, biochemistry and, increasingly, proteomics, has revealed the widespread nature of modulation of the presynaptic VGCC complex.

This book reviews and discusses the following topics:

• The fundamental role of the VGCC pore-forming Ca_Va subunit, and some of their binding partners, in presynaptic function and synaptic plasticity.
• Modulation of presynaptic Ca_Va subunits by auxiliary Ca_Vb and a₂d subunits and by their major interaction partners, such as active zone scaffolding proteins, synaptic proteins, G proteins and small GTPases, which, together, contribute to the VGCC proteome.
• Work at the cutting edge of research, including how direct electrophysiology recordings from presynaptic terminals and introduction of synthetic Ca_Va peptides into presynaptic terminals has expanded our knowledge of VGCC function.
• Evidence emerging over the last decade demonstrating that VGCC subunits represent bona fide molecular targets for therapeutic drug discovery. This development is illustrated by the introduction of the Ca_V2.2 blocker ziconotide, which represents an important proof-of-concept, but is best exemplified by the emergence of gabapentinoids, which bind the VGCC auxiliary a₂d subunit, as first-line treatments for chronic neuropathic pain.

Throughout,chapters are accompanied with illustrative Tables and Figure providing a useful and comprehensive summary of the current state-of-play in this area of significant therapeutic interest. Work described here also provides a solid basis for future research in this important area.