Dataset Information

Ca_v1.3 calcium channels are full-range linear amplifiers of firing frequencies in lateral DA SN neurons.

ABSTRACT: The low-threshold L-type calcium channel Ca_v1.3 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_v1.3 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_v1.3 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.

SUBMITTER: Shin J

PROVIDER: S-EPMC9177074 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Cav1.3 calcium channels are full-range linear amplifiers of firing frequencies in lateral DA SN neurons.

Shin Josef J Kovacheva Lora L Thomas Dominique D Stojanovic Strahinja S Knowlton Christopher J CJ Mankel Johanna J Boehm Johannes J Farassat Navid N Paladini Carlos C Striessnig Jörg J Canavier Carmen C CC Geisslinger Gerd G Roeper Jochen J

Science advances 20220608 23

The low-threshold L-type calcium channel Cav1.3 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 Cav1.3 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%. Furtherm ...[more]

PMID: 35675413

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Project description:Mammalian circadian (24 h) rhythms are timed by the pattern of spontaneous action potential firing in the suprachiasmatic nucleus (SCN). This oscillation in firing is produced through circadian regulation of several membrane currents, including large-conductance Ca2+- and voltage-activated K+ (BK) and L-type Ca2+ channel (LTCC) currents. During the day steady-state BK currents depend mostly on LTCCs for activation, whereas at night they depend predominantly on ryanodine receptors (RyRs). However, the contribution of these Ca2+ channels to BK channel activation during action potential firing has not been thoroughly investigated. In this study, we used a pharmacological approach to determine that both LTCCs and RyRs contribute to the baseline membrane potential of SCN action potential waveforms, as well as action potential-evoked BK current, during the day and night, respectively. Since the baseline membrane potential is a major determinant of circadian firing rate, we focused on the LTCCs contributing to low voltage activation of BK channels during the subthreshold phase. For these experiments, two LTCC subtypes found in SCN (CaV1.2 and CaV1.3) were coexpressed with BK channels in heterologous cells, where their differential contributions could be separately measured. CaV1.3 channels produced currents that were shifted to more hyperpolarized potentials compared with CaV1.2, resulting in increased subthreshold Ca2+ and BK currents during an action potential command. These results show that although multiple Ca2+ sources in SCN can contribute to the activation of BK current during an action potential, specific BK-CaV1.3 partnerships may optimize the subthreshold BK current activation that is critical for firing rate regulation.NEW & NOTEWORTHY BK K+ channels are important regulators of firing. Although Ca2+ channels are required for their activation in excitable cells, it is not well understood how BK channels activate using these Ca2+ sources during an action potential. This study demonstrates the differences in BK current activated by CaV1.2 and CaV1.3 channels in clock neurons and heterologous cells. The results define how specific ion channel partnerships can be engaged during distinct phases of the action potential.

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Ca_v1.3 calcium channels are full-range linear amplifiers of firing frequencies in lateral DA SN neurons.

Publications

Ca<sub>v</sub>1.3 calcium channels are full-range linear amplifiers of firing frequencies in lateral DA SN neurons.

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Cav1.3 calcium channels are full-range linear amplifiers of firing frequencies in lateral DA SN neurons.

Publications

Ca&lt;sub&gt;v&lt;/sub&gt;1.3 calcium channels are full-range linear amplifiers of firing frequencies in lateral DA SN neurons.

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OmicsDI is part of the ELIXIR infrastructure

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Ca_v1.3 calcium channels are full-range linear amplifiers of firing frequencies in lateral DA SN neurons.

Ca<sub>v</sub>1.3 calcium channels are full-range linear amplifiers of firing frequencies in lateral DA SN neurons.