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The Journal of Neuroscience, April 4, 2007, 27(14):3855-3863; doi:10.1523/JNEUROSCI.4028-06.2007

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Cellular/Molecular
Molecular Nature of Anomalous L-Type Calcium Channels in Mouse Cerebellar Granule Cells

Alexandra Koschak,^1,2 Gerald J. Obermair,³ Francesca Pivotto,¹ Martina J. Sinnegger-Brauns,² Jörg Striessnig,² and Daniela Pietrobon¹

¹Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Institute of Neuroscience, University of Padova, 35121 Padova, Italy, ²Institute of Pharmacy, Pharmacology, and Toxicology, and ³Department of Physiology and Medical Physics, Division of Physiology, Innsbruck Medical University, A-6020 Innsbruck, Austria

Correspondence should be addressed to Daniela Pietrobon at the above address. Email: daniela.pietrobon{at}unipd.it

Single-channel analysis revealed the existence of neuronal L-type Ca²⁺ channels (LTCCs) with fundamentally different gating properties; in addition to LTCCs resembling cardiac channels, LTCCs with anomalous gating were identified in a variety of neurons, including cerebellar granule cells. Anomalous LTCC gating is mainly characterized by long reopenings after repolarization following strong depolarizations or trains of action potentials. To elucidate the unknown molecular nature of anomalous LTCCs, we performed single-channel patch-clamp recordings from cerebellar granule cells of wild-type, Ca_v1.3^–/– and Ca_v1.2DHP^–/– [containing a mutation in the Ca_v1.2 ₁ subunit that eliminates dihydropyridine (DHP) sensitivity] mice. Quantitative reverse transcription-PCR revealed that Ca_v1.2 accounts for 89% and Ca_v1.3 for 11% of the LTCC transcripts in wild-type cerebellar granule cells, whereas Ca_v1.1 and Ca_v1.4 are expressed at insignificant levels. Anomalous LTCCs were observed in neurons of Ca_v1.3^–/– mice with a frequency not different from wild type. In the presence of the DHP agonist (+)-(S)-202-791, the typical prepulse-induced reopenings of anomalous LTCCs after repolarization were shorter in Ca_v1.2DHP^–/– neurons than in Ca_v1.3^–/– neurons. Reopenings in Ca_v1.2DHP^–/– neurons in the presence of the DHP agonist were similar to those in wild-type neurons in the absence of the agonist. These data show that Ca_v1.2₁ subunits are the pore-forming subunits of anomalous LTCCs in mouse cerebellar granule cells. Given the evidence that Ca_v1.2 channels are specifically involved in sustained Ras-MAPK (mitogen-activated protein kinase)-dependent cAMP response element-binding protein phosphorylation and LTCC-dependent hippocampal long-term potentiation (LTP) (Moosmang et al., 2005), we discuss the hypothesis that anomalous rather than cardiac-type Ca_v1.2 channels are specifically involved in LTCC-dependent and gene transcription-dependent LTP.

Key words: calcium channels; L-type; LTP; transgenic mice; single channel; cerebellar granule cells

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Received Sept. 15, 2006; revised Feb. 28, 2007; accepted Feb. 28, 2007.

Correspondence should be addressed to Daniela Pietrobon at the above address. Email: daniela.pietrobon{at}unipd.it

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