LRRK2 Regulates Voltage-Gated Calcium Channel Function

Voltage-gated Ca(2+) (Ca(V)) channels enable Ca(2+) influx in response to membrane depolarization. Ca(V)2.1 channels are localized to the presynaptic membrane of many types of neurons where they are involved in triggering neurotransmitter release. Several signaling proteins have been identified as important Ca(V)2.1 regulators including protein kinases, G-proteins and Ca(2+) binding proteins. Recently, we discovered that leucine rich repeat kinase 2 (LRRK2), a protein associated with inherited Parkinson’s disease, interacts with specific synaptic proteins and influences synaptic transmission. Since synaptic proteins functionally interact with Ca(V)2.1 channels and synaptic transmission is triggered by Ca(2+) entry via Ca(V)2.1, we investigated whether LRRK2 could impact Ca(V)2.1 channel function. Ca(V)2.1 channel properties were measured using whole cell patch clamp electrophysiology in HEK293 cells transfected with Ca(V)2.1 subunits and various LRRK2 constructs. Our results demonstrate that both wild type (wt) LRRK2 and the G2019S LRRK2 mutant caused a significant increase in whole cell Ca(2+) current density compared to cells expressing only the Ca(V)2.1 channel complex. In addition, LRRK2 expression caused a significant hyperpolarizing shift in voltage-dependent activation while having no significant effect on inactivation properties. These functional changes in Ca(V)2.1 activity are likely due to a direct action of LRRK2 as we detected a physical interaction between LRRK2 and the β3 Ca(V) channel subunit via coimmunoprecipitation. Furthermore, effects on Ca(V)2.1 channel function are dependent on LRRK2 kinase activity as these could be reversed via treatment with a LRRK2 inhibitor. Interestingly, LRRK2 also augmented endogenous voltage-gated Ca(2+) channel function in PC12 cells suggesting other Ca(V) channels could also be regulated by LRRK2. Overall, our findings support a novel physiological role for LRRK2 in regulating Ca(V)2.1 function that could have implications for how mutations in LRRK2 contribute to Parkinson’s disease pathophysiology.