PubMed · 10195086
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B Lindmark. 1998. Cardiac risks with beta agonists.. https://doi.org/10.1136/thx.53.12.1094
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Insulin activates a complex set of intracellular responses, including the activation of mitogen-activated protein kinases Erk1,2. The counterregulatory actions of insulin on catecholamine action are well known and include phosphorylation of the beta(2)-adrenergic receptor on Tyr(350), Tyr(354), and Tyr(364) in the C-terminal cytoplasmic domain, as well as enhanced sequestration of the beta(2)-adrenergic receptor. Both beta-adrenergic agonists and insulin provoke sequestration of beta(2)-adrenergic receptors in a synergistic manner. In the current work, cross-talk between insulin action and beta(2)-adrenergic receptors revealed that insulin activation of Erk1,2 was amplified via beta(2)-adrenergic receptors. In Chinese hamster ovary cells, expression of beta(2)-adrenergic receptors enhanced 5-10-fold the activation of Erk1,2 by insulin and prolonged the activation, the greatest enhancement occurring at 5 min post-insulin. The potentiation of insulin signaling on Erk1,2 was proportional to the level of expression of beta(2)-adrenergic receptor. The potentiation of insulin signaling requires the integrity of Tyr(350) of the beta(2)-adrenergic receptor, a residue phosphorylated in response to insulin. beta(2)-adrenergic receptors with a Y350F mutation failed to potentiate insulin activation of Erk1,2. Expression of the C-terminal domain of the beta(2)-adrenergic receptor (Pro(323)-Leu(418)) in cells expressing the intact beta(2)-adrenergic receptor acts as a dominant negative, blocking the potentiation of insulin activation of Erk1,2 via the beta(2)-adrenergic receptor. Blockade of beta(2)-adrenergic receptor sequestration does not alter the ability of the beta(2)-adrenergic receptor to potentiate insulin action on Erk1,2. We propose a new paradigm in which a G-protein-linked receptor, such as the beta(2)-adrenergic receptor, itself acts as a receptor-based scaffold via its binding site for Src homology 2 domains, facilitating signaling of the mitogen-activated protein kinase pathway by insulin.
In the present study Ca2+ entry via different voltage-dependent membrane channels was examined with a fluorescent Ca2+ indicator before and after beta-adrenergic stimulation. To clearly distinguish between Ca2+ influx and Ca2+ release from the sarcoplasmic reticulum the Ca2+ store was blocked with 0.1 microM thapsigargin and 10 microM ryanodine. Omitting Na+ from the pipette filling solution minimized Ca2+ entry via Na+-Ca2+ exchange. Individual guinea-pig ventricular myocytes were voltage clamped in the whole-cell configuration of the patch-clamp technique and different membrane currents were activated using specific voltage protocols. The intracellular Ca2+ concentration was simultaneously recorded with a laser-scanning confocal microscope using fluo-3 as a Ca2+ indicator. Ca2+ entry pathways were discriminated using pharmacological blockers under control conditions and during beta-adrenergic stimulation with 1 microM isoproterenol (isoprenaline) in the bathing solution or 100 microM cAMP in the patch-clamp pipette. Isoproterenol or cAMP potentiated the Ca2+ influx signals recorded during L-type Ca2+ current activation but, more interestingly, also during Na+ current (INa) activation. The Ca2+ influx signal arising from L-type Ca2+ current activation was usually blocked by 50 microM Cd2+. However, the Ca2+ influx signal elicited by the Na+ current activation protocol was only curtailed to 56.4 +/- 28.2 % by 100 microM Ni2+ but was reduced to 17.9 +/- 15.1 % by 50 microM Cd2+ and consistently eliminated by 5 mM Ni2+. The pronounced Cd2+ and moderate Ni2+ sensitivity of the Ca2+ influx signals suggested that the predominant source of Ca2+ influx during the Na+ current activation - before and during beta-adrenergic stimulation - was a spurious activation of the L-type Ca2+ current, presumably due to voltage escape during Na+ current activation. Calculations based on the relationship between Ca2+ current and fluorescence change revealed that, on average, we could reliably detect rapid Ca2+ concentration changes as small as 5.4 +/- 0.7 nM. Thus, we can estimate an upper limit for the Ca2+ permeability of the phosphorylated TTX-sensitive Na+ channels which is less than 0.04:1 for Ca2+ ions flowing through Na+ channels via the proposed 'slip-mode' Ca2+ conductance. Therefore the slip-mode Ca2+ conductance of Na+ channels does not contribute noticeably to the Ca2+ signals observed in our experiments.
The partial agonist activities of carteolol were investigated on atypical beta-adrenoceptors of duodenum on the guinea pig. Carteolol produced a concentration-dependent relaxation of the guinea pig duodenum (pD(2)=4.85), which was not significantly affected by propranolol (1 microM). In the presence of propranolol (1 microM), however, the non-selective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist, bupranolol (30 microM), caused a rightward shift of the concentration-response curves for carteolol (apparent pA(2)=5.31). Moreover, carteolol (10 microM) weakly, but significantly, antagonized the relaxations in response to catecholamines (isoprenaline, noradrenaline and adrenaline), to a selective beta(3)-adrenoceptor agonist, (R*, R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]pheno xyacetic acid sodium salt (BRL37344), and to a non-conventional partial beta(3)-adrenoceptor agonist, [4-[3-[(1, 1-dimethylethyl)amino]-2-hydroxypropoxy]-1, 3-dihydro-2H-benzimidazol-2-one] hydrochloride (CGP12177A), also in the guinea pig duodenum (apparent pA(2)=5.77, 5.92, 6.05, 6.56 and 5. 58, respectively). These results suggest that the partial agonist effects of carteolol are mediated by atypical beta-adrenoceptors in the guinea pig duodenum.