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The Journal of Neuroscience, February 7, 2007, 27(6):1374-1385; doi:10.1523/JNEUROSCI.5191-06.2007

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Cellular/Molecular
Erbin Enhances Voltage-Dependent Facilitation of Ca_v1.3 Ca²⁺ Channels through Relief of an Autoinhibitory Domain in the Ca_v1.3 ₁ Subunit

Irina Calin-Jageman,^1,2 Kuai Yu,^1,2 Randy A. Hall,¹ Lin Mei,³ and Amy Lee^1,2

¹Department of Pharmacology and ²Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia 30322, and ³Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics and Department of Neurology, Medical College of Georgia, Augusta, Georgia 30912

Correspondence should be addressed to Amy Lee, Department of Pharmacology, Emory University School of Medicine, 5123 Rollins Research Building, 1510 Clifton Road, Atlanta, GA 30322. Email: alee{at}pharm.emory.edu

Ca_v1.3 (L-type) voltage-gated Ca²⁺ channels have emerged as key players controlling Ca²⁺ signals at excitatory synapses. Compared with the more widely expressed Ca_v1.2 L-type channel, relatively little is known about the mechanisms that regulate Ca_v1.3 channels. Here, we describe a new role for the PSD-95 (postsynaptic density-95)/Discs large/ZO-1 (zona occludens-1) (PDZ) domain-containing protein, erbin, in directly potentiating Ca_v1.3. Erbin specifically forms a complex with Ca_v1.3, but not Ca_v1.2, in transfected cells. The significance of erbin/Ca_v1.3 interactions is supported by colocalization in somatodendritic domains of cortical neurons in culture and coimmunoprecipitation from rat brain lysates. In electrophysiological recordings, erbin augments facilitation of Ca_v1.3 currents by a conditioning prepulse, a process known as voltage-dependent facilitation (VDF). This effect requires a direct interaction of the erbin PDZ domain with a PDZ recognition site in the C-terminal domain (CT) of the long variant of the Ca_v1.3 ₁ subunit (₁1.3). Compared with Ca_v1.3, the Ca_v1.3b splice variant, which lacks a large fraction of the ₁1.3 CT, shows robust VDF that is not further affected by erbin. When coexpressed as an independent entity with Ca_v1.3b or Ca_v1.3 plus erbin, the ₁1.3 CT strongly suppresses VDF, signifying an autoinhibitory function of this part of the channel. These modulatory effects of erbin, but not ₁1.3 CT, depend on the identity of the auxiliary Ca²⁺ channel ß subunit. Our findings reveal a novel mechanism by which PDZ interactions and alternative splicing of ₁1.3 may influence activity-dependent regulation of Ca_v1.3 channels at the synapse.

Key words: L-type; voltage-gated Ca²⁺ channel; PDZ domain; facilitation; plasticity; excitability

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Received June 23, 2006; revised Dec. 27, 2006; accepted Dec. 29, 2006.

Correspondence should be addressed to Amy Lee, Department of Pharmacology, Emory University School of Medicine, 5123 Rollins Research Building, 1510 Clifton Road, Atlanta, GA 30322. Email: alee{at}pharm.emory.edu

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