Opposite Action of β1- and β2-Adrenergic Receptors on CaV1 L-Channel Current in Rat Adrenal Chromaffin Cells

Voltage-gated Ca 2+ channels of chromaffin cells are modulated by locally released neurotransmitters through autoreceptor-activated G-proteins. Clear evidence exists in favor of a Ca 2+ channel gating inhibition mediated by purinergic, opioidergic, and α-adrenergic autoreceptors. Few and contradictory data suggest also a role of β-adrenergic autoreceptors (β-ARs), the action of which, however, remains obscure. Here, using patch-perforated recordings, we show that rat chromaffin cells respond to the β-AR agonist isoprenaline (ISO) by either upmodulating or downmodulating the amplitude of Ca 2+ currents through two distinct modulatory pathways. ISO (1 μ m ) could cause either fast inhibition (∼25%) or slow potentiation (∼25%), or a combination of the two actions. Both effects were completely prevented by propranolol. Slow potentiation was more evident in cells pretreated with pertussis toxin (PTX) or when β 1 -ARs were selectively stimulated with ISO + ICI118,551. Potentiation was absent when the β 2 -AR-selective agonist zinterol (1 μ m ), the protein kinase A (PKA) inhibitor H89, or nifedipine was applied, suggesting that potentiation is associated with a PKA-mediated phosphorylation of L-channels (∼40% L-current increase) through β 1 -ARs. The ISO-induced inhibition was fast and reversible, preserved in cell treated with H89, and mimicked by zinterol. The action of zinterol was mostly on L-channels (38% inhibition). Zinterol action preserved the channel activation kinetics, the voltage-dependence of the I – V characteristic, and was removed by PTX, suggesting that β 2 AR-mediated channel inhibition was mainly voltage independent and coupled to G i /G o -proteins. Sequential application of zinterol and ISO mimicked the dual action (inhibition/potentiation) of ISO alone. The two kinetically and pharmacologically distinct β-ARs signaling uncover alternative pathways, which may serve the autocrine control of Ca 2+ -dependent exocytosis and other related functions of rat chromaffin cells.