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Inhibition of dendritic Ca 2+ spikes by GABA B receptors in cortical pyramidal neurons is mediated by a direct G i/o ‐βγ‐subunit interaction with Ca v 1 channels
Author(s) -
PérezGarci Enrique,
Larkum Matthew E.,
Nevian Thomas
Publication year - 2013
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2012.245464
Subject(s) - inhibitory postsynaptic potential , gabaergic , chemistry , neuroscience , voltage dependent calcium channel , protein subunit , receptor , glutamate receptor , gabaa receptor , biophysics , microbiology and biotechnology , biology , calcium , biochemistry , organic chemistry , gene
Key points• Voltage‐dependent Ca 2+ channels mediate a large repertoire of physiological actions, including the generation of dendritic spikes in neocortical pyramidal neurons; however, the type of Ca 2+ channels involved in their generation remains unknown. • We found that L‐type Ca 2+ currents generate the sustained plateau potential of the Ca 2+ spike. GABA B receptors inhibit Ca 2+ spikes by specifically blocking dendritic L‐type currents. • This inhibition is mediated by a direct G i/o ‐βγ‐subunit interaction with the Ca v 1 channels. • Protein kinases (protein kinase C and A) have an important influence on the generation and sustaining of dendritic Ca 2+ spikes; however, their activity is not involved in the GABA B ‐mediated inhibition of Ca 2+ spikes. • Inhibitory modulation of dendritic activity is important to understand the transformation of synaptic inputs into neuronal output activity. Our results shed light on the molecular mechanisms by which GABA acting via its GABA B receptors can exert this inhibitory action.Abstract Voltage‐dependent calcium channels (VDCCs) serve a wide range of physiological functions and their activity is modulated by different neurotransmitter systems. GABAergic inhibition of VDCCs in neurons has an important impact in controlling transmitter release, neuronal plasticity, gene expression and neuronal excitability. We investigated the molecular signalling mechanisms by which GABA B receptors inhibit calcium‐mediated electrogenesis (Ca 2+ spikes) in the distal apical dendrite of cortical layer 5 pyramidal neurons. Ca 2+ spikes are the basis of coincidence detection and signal amplification of distal tuft synaptic inputs characteristic for the computational function of cortical pyramidal neurons. By combining dendritic whole‐cell recordings with two‐photon fluorescence Ca 2+ imaging we found that all subtypes of VDCCs were present in the Ca 2+ spike initiation zone, but that they contribute differently to the initiation and sustaining of dendritic Ca 2+ spikes. Particularly, Ca v 1 VDCCs are the most abundant VDCC present in this dendritic compartment and they generated the sustained plateau potential characteristic for the Ca 2+ spike. Activation of GABA B receptors specifically inhibited Ca v 1 channels. This inhibition of L‐type Ca 2+ currents was transiently relieved by strong depolarization but did not depend on protein kinase activity. Therefore, our findings suggest a novel membrane‐delimited interaction of the G i/o ‐βγ‐subunit with Ca v 1 channels identifying this mechanism as the general pathway of GABA B receptor‐mediated inhibition of VDCCs. Furthermore, the characterization of the contribution of the different VDCCs to the generation of the Ca 2+ spike provides new insights into the molecular mechanism of dendritic computation.