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Isoform-specific regulation of mood behavior and pancreatic beta cell and cardiovascular function by L-type Ca2+ channels

Author:
  • MJ Sinnegger-Brauns
  • A Hetzenauer
  • IG Huber
  • Erik Renström
  • G Wietzorrek
  • S Berjukov
  • M Cavalli
  • D Walter
  • A Koschak
  • R Waldschutz
  • S Hering
  • S Bova
  • Patrik Rorsman
  • O Pongs
  • N Singewald
  • J Striessnig
Publishing year: 2004
Language: English
Pages: 1430-1439
Publication/Series: Journal of Clinical Investigation
Volume: 113
Issue: 10
Document type: Journal article
Publisher: American Society for Clinical Investigation

Abstract english

Ca(v)1.2 and Ca(v)1.3 L-type Ca2+ channels (LTCCs) are believed to underlie Ca2+ currents in brain, pancreatic beta cells, and the cardiovascular system. In the CNS, neuronal LTCCs control excitation-transcription coupling and neuronal plasticity. However, the pharmacotherapeutic implications of CNS LTCC modulation are difficult to study because LTCC modulators cause card iovascular (activators and. blockers) and neurotoxic (activators) effects. We selectively eliminated high dihydropyridine (DHP) sensitivity from Ca(v)1.2 alpha1 subunits (Ca(v)1.2DHP(-/-)) without affecting function and expression. This allowed separation of the DHP effects of Ca(v)1.2 from those of Ca(v)1.3 and other LTCCs. DHP effects on pancreatic P cell LTCC currents, insulin secretion, cardiac inotropy, and arterial smooth muscle contractility were lost in Ca(v)1.2DHP(-/-) mice, which rules out a direct role of Ca(v)1.3 for these physiological processes. Using Ca(v)1.2DHP(-/-) mice, we established DHPs as mood-modifying agents: LTCC activator-induced neurotoxicity was abolished and disclosed a depression-like behavioral effect without affecting spontaneous locomotor activity. LTCC activator BayK 8644 (BayK) activated only a specific set of brain areas. In the ventral striatum, BayK-induced release of glutamate and 5-HT, but not dopamine and noradrenaline, was abolished. This animal model provides a useful tool to elucidate whether Ca(v)1.3-selective channel modulation represents a novel pharmacological approach to modify CNS function without major peripheral effects.

Keywords

  • Endocrinology and Diabetes

Other

Published
  • Islet patophysiology
  • Islet cell physiology
  • ISSN: 0021-9738
Erik Renström
E-mail: erik.renstrom [at] med.lu.se

Deputy head of department

Department of Clinical Sciences, Malmö

+46 40 39 11 57

+46 40 39 11 57

Principal investigator

Islet patophysiology

+46 40 39 11 57

+46 40 39 11 57

20-3-308

33

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00