Presynaptic Calcium Channels: Structure, Regulators, and Blockers

Abstract

The central and peripheral nervous systems express multiple types of ligand and voltage-gated calcium channels (VGCCs), each with specific physiological roles and pharmacological and electrophysiological properties. The members of the Ca(v)2 calcium channel family are located predominantly at presynaptic nerve terminals, where they are responsible for controlling evoked neurotransmitter release. The activity of these channels is subject to modulation by a number of different means, including alternate splicing, ancillary subunit associations, peptide and small organic blockers, G-protein-coupled receptors (GPCRs), protein kinases, synaptic proteins, and calcium-binding proteins. These multiple and complex modes of calcium channel regulation allow neurons to maintain the specific, physiological window of cytoplasmic calcium concentrations which is required for optimal neurotransmission and proper synaptic function. Moreover, these varying means of channel regulation provide insight into potential therapeutic targets for the treatment of pathological conditions that arise from disturbances in calcium channel signaling. Indeed, considerable efforts are presently underway to identify and develop specific presynaptic calcium channel blockers that can be used as analgesics.

Regulation of N-type voltage-gated calcium channels (Cav2.2) and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons

“…From our studies and those of others, it is clear, however, that this targeting is achieved through interaction of the presynaptic Ca 2+ channel with a growing number of proteins known to be involved in synaptic vesicle exocytosis and endocytosis pathways (Catterall and Few, 2008;Chan et al, 2007;el Far et al, 1995;Evans and Zamponi, 2006;Khanna et al, 2007c;Khanna et al, 2007a;Khanna et al, 2007b;Kisilevsky and Zamponi, 2008;Stanley, 1997;Szabo et al, 2006). For example, syntaxin 1, the cardinal Cav2.2 partner protein (Sheng et al, 1994), is important for the incorporation of Ca 2+ channels into the release site apparatus.…”

An Atypical Role for Collapsin Response Mediator Protein 2 (CRMP-2) in Neurotransmitter Release via Interaction with Presynaptic Voltage-gated Calcium Channels

“…This may be due to the selective expression of N-type Ca 2ϩ channels at nascent immature terminals or in a reserve pool of terminals held in an immature state, whereas P/Qtype channels might dominate at fully mature terminals. The finding of a CRMP-2-CaV2.2 complex in adult rat brain synaptosomes 4 despite the low expression of CaV2.2 in adult brain (68) suggests that this interaction may play roles in mature nerve terminals as well. Differential expression, sorting, trafficking and targeting, postsynaptic cues, protein-protein interactions, and other factors may account for this developmental switch in Ca 2ϩ channels.…”

“…Major progress has been made toward identifying proteins of the release machinery at the transmitter release site and characterizing the effects of these proteins on synaptic transmission (1,2,4,33,(53)(54)(55)(56)(57)(58)(59)(60). Here we identify CRMP-2 as a novel "neuromodulator" of N-type Ca 2ϩ channels.…”

“…Enriched at functional release sites, CaV2.2 forms part of a large macromolecular complex, which facilitates efficient neurotransmitter release. Identification and analyses of protein-protein interactions within the nerve terminal have demonstrated a functional coupling between presynaptic Ca 2ϩ channels and the transmitter release machinery (1)(2)(3)(4). Because transmitter release is proportional to the third or fourth power of Ca 2ϩ entry (5-7), even small changes in intracellular Ca 2ϩ can elicit large changes in synaptic transmission.…”

Allosteric Modulation of Ca2+ flux in Ligand-gated Cation Channel (P2X4) by Actions on Lateral Portals

“…The Ca 2ϩ currents of ligand-gated ion channels (LGICs) 3 play essential roles in cell signaling by regulating transmitter release, muscle contraction, and gene transcription (1,2). Most cells are exquisitely sensitive to [Ca 2ϩ ] i , and thus small changes in the amplitude of ligand-gated Ca 2ϩ currents can lead to dramatic effects on the regulation of downstream Ca 2ϩ -dependent signaling processes (3).…”