The Role of Striatal Cav1.3 Calcium Channels in Therapeutics for Parkinson's Disease.

Abstract

Parkinson's disease (PD) is a relentlessly progressive neurodegenerative disorder with typical motor symptoms that include rigidity, tremor, and akinesia/bradykinesia, in addition to a host of non-motor symptoms. Motor symptoms are caused by progressive and selective degeneration of dopamine (DA) neurons in the SN pars compacta (SNpc) and the accompanying loss of striatal DA innervation from these neurons. With the exception of monogenic forms of PD, the etiology of idiopathic PD remains unknown. While there are a number of symptomatic treatment options available to individuals with PD, these therapies do not work uniformly well in all patients, and eventually most are plagued with waning efficacy and significant side-effect liability with disease progression. The incidence of PD increases with aging, and as such the expected burden of this disease will continue to escalate as our aging population increases (Dorsey et al. Neurology 68:384-386, 2007). The daunting personal and socioeconomic burden has pressed scientists and clinicians to find improved symptomatic treatment options devoid side-effect liability and meaningful disease-modifying therapies. Federal and private sources have supported clinical investigations over the past two-plus decades; however, no trial has yet been successful in finding an effective therapy to slow progression of PD, and there is currently just one FDA approved drug to treat the antiparkinsonian side-effect known as levodopa-induced dyskinesia (LID) that impacts approximately 90% of all individuals with PD. In this review, we present biological rationale and experimental evidence on the potential therapeutic role of the L-type voltage-gated Cav1.3 calcium (Ca²⁺) channels in two distinct brain regions, with two distinct mechanisms of action, in impacting the lives of individuals with PD. Our primary emphasis will be on the role of Cav1.3 channels in the striatum and the compelling evidence of their involvement in LID side-effect liability. We also briefly discuss the role of these same Ca²⁺ channels in the SNpc and the longstanding interest in Cav1.3 in this brain region in halting or delaying progression of PD.