Voltage-Activated L-Type Calcium Channels and Brain Function

Voltage-gated calcium-channels are pores in the plasma membrane of excitable cells which open upon membrane depolarization and allow calcium- ions to enter the cell. This calcium-signal controls different physiological processes, including muscle contraction and neuronal function. L-type calcium-channels in the cardiovascular system are a well established target for so-called calcium- channel blockers which are widely used clinically to treat cardiovascular diseases such as hypertension, angina and arrhythmias. L-type channels are also expressed in neurons and their role for modulating neuronal function have been well established in vitro. Despite this functional role it remains completely unclear if their selective modulation in the CNS could be exploited therapeutically for CNS diseases. We have recently developed unique mouse models that allow us to address this question. Activation of all neuronal L-type channels by dihydropyridine (DHP) calcium- channel activators causes toxicity. Instead, we found in one of our mouse models, that the activation of only one L-type channel isoform (Cav1.3) did not cause toxicity. It enhanced activity only in a few brain regions and was associated with a depressant-like behavior. This demonstrated that in this mouse model modulation of CNS function by DHPs is possible in the absence of acute toxic effects. We now want to investigate if selective activation or block of only Cav1.3 channels causes changes of CNS function as measured in behavioral studies in mice. We will especially focus on functions that have been previously been claimed to be modulated by DHPs, such as fear, drug addiction and withdrawal. These functional studies will be accompanied by a detailed analysis of the structural determinants of Cav1.3 channels to understand how Cav1.3 can give rise to different L-type currents in different cells (e.g. neurons and cochlear hair cells). These studies will include identification of additional proteins which are able to bind to Cav1.3 channels and thereby may not only stabilize its function but also contribute to the activation of intracellular signaling pathways. Our mouse models will also enable us to identify the molecular nature of so called "anomalous" L-type calcium- channels which are believed to play a major role for long-term responses of neurons to brief stimuli. Such responses are e.g. important for learning and memory. Taken together our studies will provide important structural and pharmacological information that will allow us to make predictions about the pharmacotherapeutic potential of specific blockers of L-type calcium- channel isoforms.

Voltage-gated calcium-channels are pores in the plasma membrane of excitable cells which open upon membrane depolarization and allow calcium- ions to enter the cell. This calcium-signal controls different physiological processes, including muscle contraction and neuronal function. L-type calcium-channels in the cardiovascular system are a well established target for so-called calcium- channel blockers which are widely used clinically to treat cardiovascular diseases such as hypertension, angina and arrhythmias. L-type channels are also expressed in neurons and their role for modulating neuronal function have been well established in vitro. Despite this functional role it remains completely unclear if their selective modulation in the CNS could be exploited therapeutically for CNS diseases. We have recently developed unique mouse models that allow us to address this question. Activation of all neuronal L-type channels by dihydropyridine (DHP) calcium- channel activators causes toxicity. Instead, we found in one of our mouse models, that the activation of only one L-type channel isoform (Cav1.3) did not cause toxicity. It enhanced activity only in a few brain regions and was associated with a depressant-like behavior. This demonstrated that in this mouse model modulation of CNS function by DHPs is possible in the absence of acute toxic effects. We now want to investigate if selective activation or block of only Cav1.3 channels causes changes of CNS function as measured in behavioral studies in mice. We will especially focus on functions that have been previously been claimed to be modulated by DHPs, such as fear, drug addiction and withdrawal. These functional studies will be accompanied by a detailed analysis of the structural determinants of Cav1.3 channels to understand how Cav1.3 can give rise to different L-type currents in different cells (e.g. neurons and cochlear hair cells). These studies will include identification of additional proteins which are able to bind to Cav1.3 channels and thereby may not only stabilize its function but also contribute to the activation of intracellular signaling pathways. Our mouse models will also enable us to identify the molecular nature of so called "anomalous" L-type calcium- channels which are believed to play a major role for long-term responses of neurons to brief stimuli. Such responses are e.g. important for learning and memory. Taken together our studies will provide important structural and pharmacological information that will allow us to make predictions about the pharmacotherapeutic potential of specific blockers of L-type calcium- channel isoforms.