S. Picardi, M. F. Stevens, K. Hahnenkamp, M. E. Durieux, P. Lirk, M. W

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Presentation transcript:

Time-dependent modulation of muscarinic m1/m3 receptor signalling by local anaesthetics S. Picardi, M.F. Stevens, K. Hahnenkamp, M.E. Durieux, P. Lirk, M.W. Hollmann British Journal of Anaesthesia Volume 112, Issue 2, Pages 370-379 (February 2014) DOI: 10.1093/bja/aet299 Copyright © 2014 The Author(s) Terms and Conditions

Fig 1 Modulation of m1 and m3 signalling by extracellular lidocaine in Xenopus oocytes. (a) Sample traces of ICl(Ca) induced by 10 s administration of MCh at EC50 in an oocyte expressing the m3 receptor and in the presence of lidocaine at IC50. Peak currents are 1.12 mA (a) and 0.48 mA (b). (c) Effects of long-term exposure to lidocaine (1.8 nM) on m1 signalling (n=22). Recombinant expressed m1 receptors were stimulated with MCh (0.57 µM). (d) Lidocaine (37 nM) on m3 responses, elicited by MCh (0.42 µM, n=25). Effects were determined at different time points and are shown as mean (sd), responses, normalized to corresponding control responses. *Significance (P<0.05) compared with the control group. British Journal of Anaesthesia 2014 112, 370-379DOI: (10.1093/bja/aet299) Copyright © 2014 The Author(s) Terms and Conditions

Fig 2 Functional ligand binding of recombinantly expressed m3 receptors in CHO cells. [3H]quinuclydinyl benzylate ([3H]QNB) (0.1–16 nM) binding to membranes prepared from Chinese ovarian hamster cells stably transfected with the rat muscarinic m3 receptor at different time points (n=5 at each time point). British Journal of Anaesthesia 2014 112, 370-379DOI: (10.1093/bja/aet299) Copyright © 2014 The Author(s) Terms and Conditions

Fig 3 Sites of action for LA effects on muscarinic signalling. Effects of intracellularly injected QX314 (96 μM for m1 and 45 μM for m3) on (a) m1 and (b) m3 signalling (n=25 each). Responses were elicited by stimulation with MCh (0.57 μM for m1 and 0.42 μM for m3 receptors). (c) Effects of intracellularly administered QX314 (45 μM) on m3 signalling after depletion of the Gαq-protein (n=22). (d) Effects of extracellularly applied lidocaine (37 nM) on m3 responses, induced by MCh in Gαq-depleted oocytes (n=24). Data are mean (sd), normalized to corresponding control responses. *Significance (P<0.05) compared with the control group. British Journal of Anaesthesia 2014 112, 370-379DOI: (10.1093/bja/aet299) Copyright © 2014 The Author(s) Terms and Conditions

Fig 4 PKC antagonism modulates the effect of lidocaine on muscarinic signalling. Effects of extracellularly applied lidocaine on (a) m1 and (b) m3 signalling (1.8 and 37 nM, respectively), stimulated by MCh (0.57 μM for m1 and 0.42 μM for m3 receptors) after pre-treatment with BIM (10 μM, n=25) or (c and d) CT (10 μM, n=25), for 1 h. Data are mean (sd) normalized to corresponding control responses. *Significance (P<0.05) compared with the control group. British Journal of Anaesthesia 2014 112, 370-379DOI: (10.1093/bja/aet299) Copyright © 2014 The Author(s) Terms and Conditions

Fig 5 PKC-dependent modulation of muscarinic m3 signalling by extra- and intracellular LAs. Time course of m3 responses after incubation with BIM (10 μM) or CT (10 μM), QX314 (500 μM) or the combination of QX314 (500 μM), and BIM or CT. (a) Data obtained in the presence of BIM (n=25) and (b) data when CT was used (n=25). Oocytes were pre-treated with PKC antagonists for 1 h, followed by incubation with QX314 for 48 h. Responses were elicited by MCh (at EC50). (c) Effects of intracellularly applied lidocaine on m3 signalling in Gαq-protein-depleted oocytes (n=24). Receptors were stimulated with MCh (at EC50). Data are mean (sd) normalized to corresponding control responses. British Journal of Anaesthesia 2014 112, 370-379DOI: (10.1093/bja/aet299) Copyright © 2014 The Author(s) Terms and Conditions

Fig 6 Possible mechanism of action for LA-induced biphasic effect on muscarinic signalling. Simplified scheme of muscarinic m1 and m3 receptors. LA, binding site for LAs on an extracellular receptor domain; PKC, protein kinase C; T, S, threonine/serine amino acids; and P, phosphate molecule. (a) Muscarinic receptor before long-term exposure to LAs. The receptor is in a balanced state of stimulation and inhibition. Serine/threonine-rests are available for PKC, leading to attenuation of muscarinic signalling. (b) Muscarinic receptor after long-term exposure to LAs (>2 h). LAs inhibit muscarinic signalling Gαq-protein dependently for the first 2 h. At the same time, LAs interact with an extracellular receptor domain, resulting in a change of intracellular receptor conformation. Further serine/threonine amino acids become available for phosphorylation and after the initial inhibition receptor-function is up-regulated by LAs. British Journal of Anaesthesia 2014 112, 370-379DOI: (10.1093/bja/aet299) Copyright © 2014 The Author(s) Terms and Conditions