Loss of Cav1.3 Channels Reveals the Critical Role of L-Type and BK Channel Coupling in Pacemaking Mouse Adrenal Chromaffin Cells

Autor: Emilio Carbone, Andrea Marcantoni, Joerg Striessnig, Valentina Carabelli, Satyajit Mahapatra, David Vandael, Martina J. Sinnegger-Brauns
Rok vydání: 2010
Předmět:
medicine.medical_specialty
BK channel
Indoles
Patch-Clamp Techniques
Time Factors
Calcium Channels
L-Type
Chromaffin Cells
Biophysics
Spider Venoms
Biophysical Phenomena
Membrane Potentials
Cav1.3
Mice
chemistry.chemical_compound
Pacemaker potential
Nifedipine
BAPTA
Internal medicine
Potassium Channel Blockers
medicine
Animals
Large-Conductance Calcium-Activated Potassium Channels
Paxilline
Egtazic Acid
Cells
Cultured
Chelating Agents
Mice
Knockout
Dose-Response Relationship
Drug
Ionophores
biology
General Neuroscience
Afterhyperpolarization
Articles
3-Pyridinecarboxylic acid
1
4-dihydro-2
6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-
Methyl ester
Calcium Channel Blockers
Electric Stimulation
Coupling (electronics)
Calcium Channel Agonists
Endocrinology
Gene Expression Regulation
chemistry
Adrenal Medulla
Adrenal Cortex
biology.protein
medicine.drug
Zdroj: The Journal of Neuroscience. 30:491-504
ISSN: 1529-2401
0270-6474
Popis: We studied wild-type (WT) andCav1.3−/−mouse chromaffin cells (MCCs) with the aim to determine the isoform of L-type Ca2+channel (LTCC) and BK channels that underlie the pacemaker current controlling spontaneous firing. Most WT-MCCs (80%) were spontaneously active (1.5 Hz) and highly sensitive to nifedipine and BayK-8644 (1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid, methyl ester). Nifedipine blocked the firing, whereas BayK-8644 increased threefold the firing rate. The two dihydropyridines and the BK channel blocker paxilline altered the shape of action potentials (APs), suggesting close coupling of LTCCs to BK channels. WT-MCCs expressed equal fractions of functionally active Cav1.2 and Cav1.3 channels. Cav1.3 channel deficiency decreased the number of normally firing MCCs (30%; 2.0 Hz), suggesting a critical role of these channels on firing, which derived from their slow inactivation rate, sizeable activation at subthreshold potentials, and close coupling to fast inactivating BK channels as determined by using EGTA and BAPTA Ca2+buffering. By means of the action potential clamp, in TTX-treated WT-MCCs, we found that the interpulse pacemaker current was always net inward and dominated by LTCCs. Fast inactivating and non-inactivating BK currents sustained mainly the afterhyperpolarization of the short APs (2–3 ms) and only partially the pacemaker current during the long interspike (300–500 ms). Deletion of Cav1.3 channels reduced drastically the inward Ca2+current and the corresponding Ca2+-activated BK current during spikes. Our data highlight the role of Cav1.3, and to a minor degree of Cav1.2, as subthreshold pacemaker channels in MCCs and open new interesting features about their role in the control of firing and catecholamine secretion at rest and during sustained stimulations matching acute stress.
Databáze: OpenAIRE
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