Isoform-specific regulation of mood behavior and pancreatic beta cell and cardiovascular function by L-type Ca 2+ channels.
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.
Sinnegger-Brauns
Martina J
MJ
Abteilung Pharmakologie und Toxikologie, Institut für Pharmazie, Universität Innsbruck, Austria.
Hetzenauer
Alfred
A
Huber
Irene G
IG
Renström
Erik
E
Wietzorrek
Georg
G
Berjukov
Stanislav
S
Cavalli
Maurizio
M
Walter
Doris
D
Koschak
Alexandra
A
Waldschütz
Ralph
R
Hering
Steffen
S
Bova
Sergio
S
Rorsman
Patrik
P
Pongs
Olaf
O
Singewald
Nicolas
N
Striessnig
Jörg
J
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
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