Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Erik Renström

Erik Renström

Vice-chancellor

Erik Renström

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

Summary, in 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.

Department/s

  • Diabetes - Islet Patophysiology
  • Islet cell physiology

Publishing year

2004

Language

English

Pages

1430-1439

Publication/Series

Journal of Clinical Investigation

Volume

113

Issue

10

Document type

Journal article

Publisher

Am Soc Clin Investig

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Islet Patophysiology
  • Islet cell physiology

ISBN/ISSN/Other

  • ISSN: 0021-9738