Critical issues in establishing the coupling between
nNAChRs and L-type (Cav1) calcium channels while using a
pharmacological approach
The phenylalkylamine (verapamil), dihydropyridine (nitrendipine) and
benzothiazepine classes of Cav1 type calcium channel
blockers are capable of blocking nNAChRs (Houlihan et al., 2000; Wheeler
et al., 2006). The absence of the effects of nicotine (both on the
calcium transient and on the QC) after the application of verapamil and
nitrendipine may well be related to simple direct blockade of nNAChRs
(sensitive to DHβE and permeable to Ca2+). Indeed,
DHβE, verapamil and nitrendipine all lead to a decrease in the
transients. At the same time, all three pharmacological agents abolish
the effect of nicotine.
If even direct block of nNAChRs by verapamil and nitrendipine does take
place, a number of additional facts still point to the involvement of
the Cav1 calcium channels in the mechanism of modulation
of calcium entry and the process of ACh release in the nerve terminal.
So, after application of all three agents, the calcium entry decreases,
however, the effect of verapamil and nitrendipine is almost two times
more pronounced than that of DHβE. Further on, the QC does not change
after the addition of DHβE, whereas in the presence of verapamil and
nitrendipine it is decreased by more than 10%. In addition, activation
of cholinergic receptors (by nicotine) and presumed blockade of
cholinergic receptors (by verapamil and nitrendipine) have not an
opposite, but a unidirectional effect - a decrease in the QC. And the
last but not the least, the absence of the effect of nicotine on the
calcium transient after application of cadmium, which does not affect
the functioning of nNAChRs (including α4β2 nNAChRs) or even potentiates
them (Wheeler et al., 2006; Garduño et al., 2012), indicates that in our
case a pharmacological effect on two different targets takes place.