title: Isoform-specific regulation of mood behavior and pancreatic beta cell and cardiovascular function by L-type Ca 2+ channels.
abstract: Ca(v)1.2 and Ca(v)1.3 L-type Ca(2+) channels (LTCCs) are believed to underlie Ca(2+) 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 cardiovascular (activators and blockers) and neurotoxic (activators) effects. We selectively eliminated high dihydropyridine (DHP) sensitivity from Ca(v)1.2 alpha 1 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 beta 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.
authors.affiliation: Abteilung Pharmakologie und Toxikologie, Institut für Pharmazie, Universität Innsbruck, Austria.
authors.forename: Martina J
authors.initials: MJ
authors.lastname: Sinnegger-Brauns
authors.forename: Alfred
authors.initials: A
authors.lastname: Hetzenauer
authors.forename: Irene G
authors.initials: IG
authors.lastname: Huber
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
authors.forename: Georg
authors.initials: G
authors.lastname: Wietzorrek
authors.forename: Stanislav
authors.initials: S
authors.lastname: Berjukov
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cavalli
authors.forename: Doris
authors.initials: D
authors.lastname: Walter
authors.forename: Alexandra
authors.initials: A
authors.lastname: Koschak
authors.forename: Ralph
authors.initials: R
authors.lastname: Waldschütz
authors.forename: Steffen
authors.initials: S
authors.lastname: Hering
authors.forename: Sergio
authors.initials: S
authors.lastname: Bova
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Olaf
authors.initials: O
authors.lastname: Pongs
authors.forename: Nicolas
authors.initials: N
authors.lastname: Singewald
authors.forename: Jörg
authors.initials: J
authors.lastname: Striessnig
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000339:Affect / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002320:Cardiovascular Physiological Phenomena; D004095:Dihydropyridines / Q000494:pharmacology; D007515:Islets of Langerhans / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; C419385:L-type calcium channel alpha(1C); D020033:Protein Isoforms; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester