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

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Abstract

Cav1.2 and Cav1.3 L-type Ca2+ channels (LTCCs) are believed to underlie Ca2+ currents in brain, pancreatic β 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 Cav1.2 α1 subunits (Cav1.2DHP–/–) without affecting function and expression. This allowed separation of the DHP effects of Cav1.2 from those of Cav1.3 and other LTCCs. DHP effects on pancreatic β cell LTCC currents, insulin secretion, cardiac inotropy, and arterial smooth muscle contractility were lost in Cav1.2DHP–/– mice, which rules out a direct role of Cav1.3 for these physiological processes. Using Cav1.2DHP–/– 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 Cav1.3-selective channel modulation represents a novel pharmacological approach to modify CNS function without major peripheral effects.

Authors

Martina J. Sinnegger-Brauns, Alfred Hetzenauer, Irene G. Huber, Erik Renström, Georg Wietzorrek, Stanislav Berjukov, Maurizio Cavalli, Doris Walter, Alexandra Koschak, Ralph Waldschütz, Steffen Hering, Sergio Bova, Patrik Rorsman, Olaf Pongs, Nicolas Singewald, Jörg Striessnig