Inhibition of dendritic Ca2+ spikes by GABAB receptors in cortical pyramidal neurons is mediated by a direct Gi/o-[beta][gamma]-subunit interaction with Cav1 channels

• Published in: The Journal of physiology 2013-04, Vol.591 (7), p.1599
• Main Authors: Perez-Garci, Enrique, Larkum, Matthew E, Nevian, Thomas
• Format: Article
• Language: English
• Subjects: Gene expression; Kinases; Neurons; Physiology; Proteins
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2012.245464

Key points * Voltage-dependent Ca2+ channels mediate a large repertoire of physiological actions, including the generation of dendritic spikes in neocortical pyramidal neurons; however, the type of Ca2+ channels involved in their generation remains unknown. * We found that L-type Ca2+ currents generate the sustained plateau potential of the Ca2+ spike. GABAB receptors inhibit Ca2+ spikes by specifically blocking dendritic L-type currents. * This inhibition is mediated by a direct Gi/o-[beta][gamma]-subunit interaction with the Cav1 channels. * Protein kinases (protein kinase C and A) have an important influence on the generation and sustaining of dendritic Ca2+ spikes; however, their activity is not involved in the GABAB-mediated inhibition of Ca2+ 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 GABAB 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 GABAB receptors inhibit calcium-mediated electrogenesis (Ca2+ spikes) in the distal apical dendrite of cortical layer 5 pyramidal neurons. Ca2+ 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 Ca2+ imaging we found that all subtypes of VDCCs were present in the Ca2+ spike initiation zone, but that they contribute differently to the initiation and sustaining of dendritic Ca2+ spikes. Particularly, Cav1 VDCCs are the most abundant VDCC present in this dendritic compartment and they generated the sustained plateau potential characteristic for the Ca2+ spike. Activation of GABAB receptors specifically inhibited Cav1 channels. This inhibition of L-type Ca2+ 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 Gi/o-[beta][gamma