The extracellular calcium-sensing receptor (CaSR) is widely distributed in the brain, is modulated by changes in the external calcium concentration ([Ca2+]o), and impacts neuronal activity in a number of ways. In addition to inhibiting a non-selective cation channel in nerve terminals, inhibiting action potential evoked transmitter release, and stimulating spontaneous neurotransmission, all of which may change the predisposition for seizures to occur, it has also been proposed that CaSR transduces calcium-mediated changes in neuronal excitability. The questions to be addressed are, what are the detailed mechanisms by which CaSR signaling change result in changes of neuronal activity and does CaSR activation impact seizures? In addition as part of this proposal we will determine: 1) if CaSR activation impacts spontaneous and evoked transmission equally, 2) if CaSR signaling is the pathway that mediates [Ca2+]o-dependent changes in neuronal excitability, and 3) which of these changes is likely to mediate an antiepileptic action of CaSR agonists? The hypothesis is that CaSR, a G-protein coupled receptor (GPCR), is an important target for novel antiepileptic drugs. The proposed project is designed to test this hypothesis and determine the mechanism by which the CaSR mutations affect CaSR signaling and neuronal activity using the following four-part approach. First, it will be determined how wild-type and mutant CaSR affect the excitability of neocortical neurons in response to changes in [Ca2+]o. These experiments will employ biophysical measurements from single neurons that are expressing wt CaSR. Second we will use direct recordings from nerve terminals to determine if CaSR signaling at the terminal and soma use the same mechanisms. Third we will determine how CaSR signaling impacts neuron-neuron communication. Here experiments will allow comparison of the effects of CaSR signaling on evoked and spontaneous transmission at inhibitory and excitatory synapses. Fourth we will evaluate if CaSR agonists reduce seizures in two mouse models. Successful completion of this proposal will substantially impact the field by increasing our understanding of calcium regulation in the brain and expanding our understanding of how CaSR signaling might be utilized to treat epilepsy and other forms of seizures.

Public Health Relevance

About two million people in the USA have epilepsy (Browne and Holmes 2001) making this disease a substantial public health problem. Stroke and brain tumor are two common causes that especially impact elderly Veterans (Hope, Zeber et al. 2009) but traumatic brain injury is another cause that has resulted in Veterans being disproportionately at risk of epilepsy (Lowenstein 2009). The need for new medicines is underlined by the failure of currently available antiepileptic drugs to control seizures in 30% of people and the considerable untoward effects of many of the available medications (Kwan and Brodie 2000). In an effort to develop new treatments for patients with epilepsy, we have set out to characterize a signaling pathway that plays a role in epilepsy and thus may constitute a new drug target. The proposed studies may determine how signaling at this receptor might be utilized to treat the forms of epilepsy experienced by Veterans.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology B (NURB)
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Portland VA Medical Center
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Mattheisen, Glynis B; Tsintsadze, Timur; Smith, Stephen M (2018) Strong G-Protein-Mediated Inhibition of Sodium Channels. Cell Rep 23:2770-2781
Williams, Courtney L; Smith, Stephen M (2018) Calcium dependence of spontaneous neurotransmitter release. J Neurosci Res 96:335-347
Tsintsadze, Timur; Williams, Courtney L; Weingarten, Dennis J et al. (2017) Distinct Actions of Voltage-Activated Ca2+ Channel Block on Spontaneous Release at Excitatory and Inhibitory Central Synapses. J Neurosci 37:4301-4310
Jones, Brian L; Smith, Stephen M (2016) Calcium-Sensing Receptor: A Key Target for Extracellular Calcium Signaling in Neurons. Front Physiol 7:116