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The Journal of Neuroscience, January 1, 2003, 23(1):73-83

Opposite Action of 1- and 2-Adrenergic Receptors on Ca_V1 L-Channel Current in Rat Adrenal Chromaffin Cells

T. Cesetti^*, J. M. Hernández-Guijo^*, P. Baldelli, V. Carabelli, and E. Carbone

Department of Neuroscience, INFM Research Unit, 10125 Turin, Italy

Voltage-gated Ca²⁺ channels of chromaffin cells are modulated by locally released neurotransmitters through autoreceptor-activated G-proteins. Clear evidence exists in favor of a Ca²⁺ channel gating inhibition mediated by purinergic, opioidergic, and -adrenergic autoreceptors. Few and contradictory data suggest also a role of -adrenergic autoreceptors (-ARs), the action of which, however, remains obscure. Here, using patch-perforated recordings, we show that rat chromaffin cells respond to the -AR agonist isoprenaline (ISO) by either upmodulating or downmodulating the amplitude of Ca²⁺ currents through two distinct modulatory pathways. ISO (1 µM) 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 ₁-ARs were selectively stimulated with ISO + ICI118,551. Potentiation was absent when the ₂-AR-selective agonist zinterol (1 µM), 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 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 ₂AR-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 -ARs signaling uncover alternative pathways, which may serve the autocrine control of Ca²⁺-dependent exocytosis and other related functions of rat chromaffin cells.

Key words: 2-adrenergic receptor; 1-adrenergic receptor; voltage-gated calcium channel; cAMP/PKA signaling; G-protein-coupled receptors; adrenal medullas; zinterol

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^* T.C. and J.M.H.-G. contributed equally to this work.

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Copyright © 2003 Society for Neuroscience  0270-6474/03/23173-11$05.00/0

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