Ca _v 1.3 calcium channels are full-range linear amplifiers of firing frequencies in lateral DA SN neurons

Abstract

The low-threshold L-type calcium channel Ca v 1.3 accelerates the pacemaker rate in the heart, but its functional role for the extended dynamic range of neuronal firing is still unresolved. Here, we show that Ca v 1.3 calcium channels act as unexpectedly simple, full-range linear amplifiers of firing rates for lateral dopamine substantia nigra (DA SN) neurons in mice. This means that they boost in vitro or in vivo firing frequencies between 2 and 50 hertz by about 30%. Furthermore, we demonstrate that clinically relevant, low nanomolar concentrations of the L-type channel inhibitor isradipine selectively reduce the in vivo firing activity of these nigrostriatal DA SN neurons at therapeutic plasma concentrations. Thus, our study identifies the pacemaker function of neuronal Ca v 1.3 channels and provides direct evidence that repurposing dihydropyridines such as isradipine is feasible to selectively modulate the in vivo activity of highly vulnerable DA SN subpopulations in Parkinson’s disease.

Comparing tonic and phasic dendritic calcium in cholinergic pedunculopontine neurons and dopaminergic substantia nigra neurons

“…Overall, the effects of nifedipine on AP characteristics are consistent with the idea that SNc neurons predominantly express low-threshold subtypes and PPN neurons high-threshold subtypes of L-type Ca 2+ channels. Dopaminergic neurons of the SNc are highly heterogeneous (Evans et al, 2020;Poulin et al, 2014;Shin et al, 2022;Wu et al, 2019) and small differences in channel expression can determine whether blocking L-type channels reduces pacemaking frequency or not (Drion et al, 2011). Interestingly, we observed heterogeneity within PPN cholinergic neuron responses to nifedipine treatment.…”

“…Dopaminergic neurons of the SNc are highly heterogeneous (Evans et al, 2020; Poulin et al, 2014; Shin et al, 2022; Wu et al, 2019) and small differences in channel expression can determine whether blocking L‐type channels reduces pacemaking frequency or not (Drion et al, 2011). Interestingly, we observed heterogeneity within PPN cholinergic neuron responses to nifedipine treatment.…”

“…The pacemaking activity of SNc dopaminergic neurons is well characterized (Grace & Onn, 1989; Johnson et al, 1992). It is accompanied by large somatodendritic Ca 2+ oscillations primarily mediated by low‐threshold L‐type Ca 2+ channels (Chan et al, 2007; Guzman et al, 2009; Hage & Khaliq, 2015; Shin et al, 2022). Because this chronic Ca 2+ load adds to metabolic cost (Surmeier et al, 2010) and contributes to mitochondrial oxidative stress (Dryanovski et al, 2013; Guzman et al, 2010), L‐type Ca 2+ channel blockers have been investigated as treatment to slow the progress of PD in animal models (Liss & Striessnig, 2019; Ortner, 2021) and in clinical trials (Parkinson Study Group STEADY‐PD III Investigators, 2020; Surmeier et al, 2022).…”

Coupled action potential and calcium dynamics underlie robust spontaneous firing in dopaminergic neurons

“…This suggest that T-type Ca 2+ currents are secondary to the current through the L-type channel. Other channels that facilitate a calcium influx, such as the N-type and P/Q-type, as well as different subtypes of the L-type channel such as CaV 1.2 and CaV 1.3, have also been suggested to play a role in modulating firing in DA neurons [4,62,63]. All these have different voltage activation/inactivation threshold and may interact to modulate the firing frequency in complicated manners beyond the scope of this work.…”

Novel protocol for multiple-dose oral administration of the L-type Ca 2+ channel blocker isradipine in mice: A dose-finding pharmacokinetic study

“…These drugs have a short plasma half-life especially in rodents [ 7 ], and show high first-pass metabolism upon oral application. They have therefore been mostly delivered through parenteral routes in vivo , either directly, or through osmotic minipumps or subcutaneous drug-releasing pellets (e.g [ 8–12 ]). Pharmacokinetic data measuring the C PL achieved with these applications are sparse [ 8 , 10 , 12 , 13 ].…”