D1 Receptors Physically Interact with N-Type Calcium Channels to Regulate Channel Distribution and Dendritic Calcium Entry

Gerald W. Zamponi,Jawed Hamid,Lina Chen,Mircea C. Iftinca,Alexandra E. Kisilevsky,Shahid Hameed,Christophe Altier,Sean J. Mulligan,Brian A. MacVicar,Chao Tai,Diego Varela

doi:10.1016/j.neuron.2008.03.002

Gerald W. Zamponi, Jawed Hamid

Open Access

https://doi.org/10.1016/j.neuron.2008.03.002

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Abstract

Dopamine signaling through D1 receptors in the prefrontal cortex (PFC) plays a critical role in the maintenance of higher cognitive functions, such as working memory. At the cellular level, these functions are predicated to involve alterations in neuronal calcium levels. The dendrites of PFC neurons express D1 receptors and N-type calcium channels, yet little information exists regarding their coupling. Here, we show that D1 receptors potently inhibit N-type channels in dendrites of rat PFC neurons. Using coimmunoprecipitation, we demonstrate the existence of a D1 receptor-N-type channel signaling complex in this region, and we provide evidence for a direct receptor-channel interaction. Finally, we demonstrate the importance of this complex to receptor-channel colocalization in heterologous systems and in PFC neurons. Our data indicate that the N-type calcium channel is an important physiological target of D1 receptors and reveal a mechanism for D1 receptor-mediated regulation of cognitive function in the PFC.

Highlights

In the mammalian brain, the major catecholamine neurotransmitter dopamine (DA) plays an instrumental role in the regulation of physiological functions, including locomotion, cognition, emotion, and endocrine function (Jackson and Westlind-Danielsson, 1994; Koshikawa, 1994; Missale et al, 1998; Wise and Rompre, 1989)
The D1 receptor (D1R) is the principal target of DA signaling in the prefrontal cortices (PFC) and plays a critical role in the maintenance of higher cognitive functions, such as working memory (Brozoski et al, 1979; Goldman-Rakic, 1992; Seamans et al, 1995; Simon, 1981), yet the cellular mechanisms by which this is accomplished remain unclear
D1Rs Mediate Cav2.2 Channel Inhibition in PFC Neurons The PFC is a brain region that is critical for high-level executive functions, such as working memory, planning, and attention (Fuster, 2000)

Summary

Introduction

The major catecholamine neurotransmitter dopamine (DA) plays an instrumental role in the regulation of physiological functions, including locomotion, cognition, emotion, and endocrine function (Jackson and Westlind-Danielsson, 1994; Koshikawa, 1994; Missale et al, 1998; Wise and Rompre, 1989). The D1 receptor (D1R) is the principal target of DA signaling in the PFC and plays a critical role in the maintenance of higher cognitive functions, such as working memory (Brozoski et al, 1979; Goldman-Rakic, 1992; Seamans et al, 1995; Simon, 1981), yet the cellular mechanisms by which this is accomplished remain unclear. Numerous lines of evidence indicate that the intracellular concentration of calcium is a critical parameter for synaptic plasticity and the induction of mnemonic processes (Cull-Candy et al, 2006). This raises the possibility that the action of DA on PFC function results from its ability to alter activity-dependent changes in intracellular calcium levels. The molecular composition of these channels and the intracellular signaling mechanisms through which DA may affect calcium influx have not been determined

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