Leucine-Rich Tekrar Kinaz 2 Varyant LRRK2<sup>G2019S</sup> Yukarı-Regülatörler L-Type (CaV1.3) Kalsiyum Kanal Ca<sub>V</sub> ⁇ <3</sub> Altbirimdeki Rol:

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Voltage-gated Ca2+ (CaV) channels are transmembrane proteins comprising the pore-forming subunit CaVα1 and the ancillary proteins CaVα2δ and CaVβ. They are expressed in various tissues, including the nervous system, where they regulate Ca2+ entry in response to membrane potential changes. The increase in intracellular Ca2+ allows for regulating cell excitability and releasing neurotransmitters, among other cellular events. Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine kinase involved in vesicular mobilization. Previously, it has been shown that LRRK2 regulates neurotransmission by phosphorylating the CaVβ auxiliary subunit of the CaV2.1 (P/Q-type) presynaptic channels. However, it is unknown whether the kinase can regulate the activity of other CaV channel subtypes, such as CaV1.3 (L-type), which play a significant role in the excitability of dopaminergic neurons in the substantia nigra pars compacta (SNc) and whose dysregulation contributes to neurodegeneration in Parkinson's disease (PD). Here, we found potential phosphorylation sites for LRRK2 in CaVβ3 and examined how these molecules interact. We used immunoprecipitation and electrophysiology in HEK-293 cells expressing recombinant CaV1.3 channels, both with and without wild-type LRRK2 or its LRRK2G2019S mutation, which plays a role in familial PD through a possible gain-of-toxic-function mechanism. Our results show that LRRK2G2019S significantly increases current density through CaV1.3 channels, and this effect depends on the presence of CaVβ3. Site-directed mutagenesis revealed that phosphorylation at S152 in the sequence of CaVβ3 is necessary and sufficient to explain the abnormal regulation of the channels mediated by LRRK2G2019S. These data provide new insights into the molecular regulation that mutant LRRK2 may exert on L-type CaV1.3 channels, which determine pacemaker activity in dopaminergic neurons of the SNc and may, therefore, play a relevant role in the molecular pathophysiology of PD.

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