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Rôle des canaux calciques de type l cav1.3 et des canaux potassiques activés par les protéines g ikach dans la régulation cholinergique de l'automatisme cardiaque

Abstract : Cardiac automaticity is generated in the sino-atrial node by specialized cardiomyocytes called "pacemaker" cells. Spontaneous activity is permanently controlled by the autonomic nervous system, which regulates its frequency. Sympathetic regulation is mediated by beta1/2 receptors and cholinergic regulation by acetylcholine (ACh)-dependent activation of M2 muscarinic receptors. M2 receptors are coupled to a Gi protein. When muscarinic receptors are activated, the beta gamma subunit directly activates GIRK1/4 channels thereby opening K+ IKACh current, whereas the alpha i subunit inhibits adenylate cyclase (AC) activity. Inhibition of AC decreases intracellular cAMP production affecting directly (via the cyclic nucleotide binding domain, CNBD, of HCN channels) or indirectly via protein Kinase A (PKA) the activity of voltage-gated ion channels involved in cardiac pacing, mainly HCN4 (underlying the If current) and L-type Ca2+ channels (ICa,L). Two isoforms of L-type Ca2+ channels are expressed in pacemaker cells of the sinus node: Cav1.2 and Cav1.3. However, only Cav1.3 channels are open at low diastolic voltages, thus providing an inward current during diastolic depolarization. L-type Cav1.3 channels are therefore a potentially important effector of cholinergic regulation of cardiac pacemaker activity.I have employed the patch-clamp technique, isolated Langendorff-perfused hearts and in vivo telemetric recordings of electrocardiogram to study the role of Cav1.3 and IKACh in cholinergic regulation of pacemaker activity. I found that concomitant ablation of ICaL carried by Cav1.3 and IKACh carried by GIRK1/4 prevents cholinergic regulation after beta-adrenergic stimulation. These data show strong functional interaction between Cav1.3 and GIRK1/4 in cholinergic regulation of pacemaking. In addition, we show that Cav1.3 and Cav1.2 are both sensitive to acetylcholine, however Cav1.3 display sensitivity to low doses while Cav1.2 to high doses.In conclusion, L-type Cav1.3 channels play an important role in cholinergic regulation of pacemaking together with GIRK1/4 underlying IKACh.
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Submitted on : Friday, September 17, 2021 - 4:44:09 PM
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Leïla Talssi. Rôle des canaux calciques de type l cav1.3 et des canaux potassiques activés par les protéines g ikach dans la régulation cholinergique de l'automatisme cardiaque. Sciences agricoles. Université Montpellier, 2021. Français. ⟨NNT : 2021MONTT022⟩. ⟨tel-03348038⟩

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