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LRRK2 Regulates Voltage-Gated Calcium Channel Function.

Cade Bedford1, Catherine Sears1, Maria Perez-Carrion2

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|June 1, 2016
PubMed
Summary

Leucine rich repeat kinase 2 (LRRK2) directly regulates voltage-gated calcium (CaV2.1) channels, increasing Ca(2+) influx and influencing neuronal function. This discovery offers new insights into LRRK2

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Channel Physiology

Background:

  • Voltage-gated calcium (CaV) channels, particularly CaV2.1, are crucial for neurotransmitter release at neuronal synapses.
  • Leucine rich repeat kinase 2 (LRRK2) is implicated in inherited Parkinson's disease and has been linked to synaptic transmission.
  • Existing knowledge suggests various proteins regulate CaV2.1 channels, but LRRK2's role was previously uncharacterized.

Purpose of the Study:

  • To investigate the potential impact of leucine rich repeat kinase 2 (LRRK2) on the function of CaV2.1 channels.
  • To determine if LRRK2 physically interacts with CaV2.1 channel subunits.
  • To explore the kinase activity-dependent effects of LRRK2 on CaV2.1 channel function.

Main Methods:

  • Whole-cell patch-clamp electrophysiology was employed in HEK293 cells co-expressing CaV2.1 subunits and LRRK2 constructs.
  • Co-immunoprecipitation assays were used to detect physical interactions between LRRK2 and CaV2.1 channel β3 subunits.
  • LRRK2 kinase activity was modulated using specific inhibitors to assess its role in regulating CaV2.1 channel function.

Main Results:

  • Both wild-type and mutant G2019S LRRK2 significantly increased CaV2.1-mediated whole-cell calcium currents.
  • LRRK2 expression induced a hyperpolarizing shift in CaV2.1 channel activation voltage, without affecting inactivation.
  • Physical interaction between LRRK2 and the CaV2.1 β3 subunit was confirmed, and LRRK2's effects were dependent on its kinase activity.

Conclusions:

  • LRRK2 directly modulates CaV2.1 channel function, enhancing calcium influx and altering activation kinetics.
  • The observed physical interaction and kinase-dependent effects suggest a direct regulatory mechanism.
  • These findings reveal a novel role for LRRK2 in synaptic physiology and may have implications for Parkinson's disease pathogenesis.