Calcium channels N-type

Mackie K, Hille B. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci 1992 89 3825-3829. 

Ikeda, S. R. and Dunlap, K., Voltage-dependent modulation of N-type calcium channels role of G-protein subunits, Adv. Second Messenger Phosphoprotein Res., 33, 131-151, 1999. 

A series of 2-amino-3/4-dihydro quinazolines have been extensively explored as selective T-type calcium channel antagonists. A recent disclosure included KYS05090 (9) with an IC50 of 41 nM on the Cav3.1 subtype of the T-type channel and 120-fold selectivity versus the N-type calcium channel Cav2.2 [55]. A pharmacophore model was recently published based on this and related structures [56], but no other selectivity or in vivo activity have been disclosed since the original report. 

A structurally diverse array of N-type calcium channel antagonists has been reported, and two recent extensive reviews have summarized the structures and associated data through 2008 [59,60]. Among these... 

The benzhydryl substituent is common to many reported N-type calcium channel blockers. A recently reported series derived from the neuroepileptic flunarizine (5), which exhibits N-type calcium channel potency in a whole-cell patch-clamp assay (IC50 0.08 iM) as well as L-type potency... 

Boehm, S. and Huck, S. Inhibition of N-type calcium channels the only mechanism by which presynaptic alpha 2-autoreceptors control sympathetic transmitter release. Eur J. Neurosci. 8 1924-1931,1996. 

There are at least five different types of voltage-dependent Ca2+ channel molecules, differing in their gating kinetics, modes of Ca2+-inactivation and Ca2+-iregulation, and sensitivity to specific marine toxins [13] (see Ch. 6). The distinctions between the types of channel are of considerable interest because the different subtypes are believed to subserve different cellular functions. For example, the control of neurotransmitter release in peripheral sympathetic neurons appears to be under the predominant control of N-type calcium channels. 

These compounds block N-type calcium channels in human neuroblastoma IMR-32 cells. PD-151307 (IC50 = 0.22 pM) shows about 40-fold selectivity for N- over L-type calcium channels (IC50 = 9.1 pM in GH3 cells). These compounds may also be potentially useful in the treatment of cerebral ischemia and chronic intractable pain. 

Atanassoff, P.G., Hartmannsgruber, M.W.B., Thrasher, J., Wermeling, D., Longton, W., Gaeta, R., Singh, T., Mayo, M., McGuire, D., Luther, R.R. Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain, Reg. Anesth. Pain Med. 2000, 25, 274-278. 

Cox, B., Denyer, J.C. N-type calcium channel blockers in pain and stroke, Exp. Opin. Ther. Patents 1998, 8, 1237-1250. 

Malmberg, A.B. and Yaksh, T.L. Effect of continuous intrathecal infusion of co-conopeptides, N-type calcium-channel blockers, on behavior and antinociception in the formalin and hot-plate tests in rats, Pain 1995, 60, 83-90. 

L-type calcium channels are the primary trigger for excitation-contraction (EC) coupling in cardiac, skeletal, and smooth muscles (Bean, 1989). They are also found in most central and peripheral neurons where they in part control calcium-dependent gene expression, as well as in endocrine cells and many types of non-excitable cells where they contribute to a variety of processes including exocytotic release. Unlike most synapses in the brain and spinal cord that rely on P/Q- and N-type calcium channels for neurotransmitter release, (Wheeler et al., 1994), the presynaptic terminals in photoreceptor cells rely on the Cav1.4 (a1F) L-type calcium channel for mediating glutamate release (Tachibana et al., 1993 Nachman-Clewner et al., 1999). Photoreceptor neurotransmission is atypical first,... 

McEnery MW, Copeland TD, Vance CL (1998) Altered expression and assembly of N-type calcium channel alphalB and beta subunits in epileptic lethargic (lh/lh) mouse. J Biol Chem 273 21435-21438. 

Snutch TP (2005) Targeting chronic and neuropathic pain the N-type calcium channel comes of age. NeuroRx 2 662-670. 

Aga IVA and ro-conotoxin GVIA are standard tools in elucidating the roles of P/Q-type and N-type calcium channels in synaptic transmission. In many types of synapses, application of either toxin may mediate moderate inhibition of neurotransmitter release, whereas co-application of both blockers may almost abolish synaptic transmission due to the nonlinear dependence of synaptic release on intracellular calcium concentration. On a final note, we should add that there are many other species of cone snails and spiders that produce active toxins which selectivity inhibit specific calcium channel subtypes (for example, co-conotoxins GVIB, GVIC, GVIIA, SVIA, SVIB), and it is likely that many more remain to be discovered (Olivera et al. 1994). 

Our group also identified a second action of syntaxin 1A (but not IB) on N-type calcium channels. Co-expression of this protein with N-type calcium channels results in a tonic G protein-mediated inhibition of channel activity that does not involve receptor activation (Jarvis et al. 2000). This appears to be due to a syntaxin-mediated co-localization of the channel and Gpy that ultimately culminates in tonic channel inhibition (Figure 3ii). Indeed, syntaxin 1A binds to Gpy in vitro on a region that is distinct from the Gpy site involved in interactions with the synprint motif. These data are consistent with the idea of a sandwich formed by the channel, syntaxin and Gpy (Jarvis et al. 2002). Intriguingly, although syntaxin IB can also bind to Gpy in vitro, no tonic G protein inhibition of channel activity ensues (Lu et al. 2001). This suggests that, compared with syntaxin 1A, syntaxin IB adopts a slightly different channel-bound conformation. The syntaxin-mediated effect on G protein inhibition appears to be much more robust than the effect on channel... 

It is worth noting that the binding interaction between synaptic proteins and GPy may allow G proteins to regulate synaptic activity independently of N-type channel activity. Taken together, the interactions between calcium channels, G proteins, kinases, and synaptic proteins such as syntaxin provide for complex mechanisms that regulate N-type calcium channel activity both in expression systems and in neurons. 

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