The classic idea that receptors and/or ion channels constitute isolated entities that lie within the phospholipid bilayer of neuronal membranes is untenable. A large amount of studies now indicate that receptors and ion channels exist as dynamically assembled macromolecular complexes that localize into discrete microdomains of the neuronal plasma membrane. This brings a main focus of the research in our laboratory to characterizing the composition of the macromolecular signalling complexes and other interacting proteins that impinge in the physiological effects mediated by neurotransmitter receptors.
Our hypothesis is that receptors have subcellular localization patterns similar to those of their effector ion channels and other associated signalling molecules. Understanding how activation of various receptors can lead to modulation of ion channels is important for illustrating the physiological mechanism of this regulation in normal and pathological conditions. We study two different receptor/ion channel complexes:

1) GABAB receptors and effector ion channels: GABAB receptors control the activity of effector ion channels. The primary presynaptic target of GABAB receptors is thought to be the voltage-gated Ca2+ channel. G protein-dependent inhibition of this target reduces the influx of Ca2+ into the terminal, leading to decreased neurotransmitter release. The primary postsynaptic target of GABAB receptors is thought to be the G protein-gated inwardly-rectifying K+ (GIRK) channel, giving rise to a postsynaptic hyperpolarization. This G protein signalling can be regulated by a family of proteins called regulators of G protein signalling (RGS), which increase the GTP hydrolase activity of Gα. RGS proteins comprise a large family that contains more than 30 members, which seem to be expressed in a cell-type and protein-protein specific manner. The action and regulation of G proteins and RGS proteins is essential for normal functioning of a wide range of fundamental processes including cell division, neuronal excitability, photoreception, angiogenesis, vasoconstriction and addiction, and they are emerging as attractive therapeutic targets.

2) SK channels, NMDA receptors and other Ca2+ sources: Small conductance Ca2+-activated K+ (SK) channels are insensitive to voltage and only activated by intracellular Ca2+ ions. The SK channel family is composed of three independent genes: SK1, SK2 and SK3, codifying for three subunits with the same name, which are highly expressed in the brain. They can ensemble in the plasma membrane forming homo- or heterotetramers that provide different functional properties. SK channels play a unique role in the regulation of neuronal excitability, as well as in a number of pathological conditions like cognitive dysfunctions, epilepsy, ataxia or schizophrenia. We have demonstrated that synaptic SK2 channels are molecularly and functionally associated with NMDA receptors, but SK2 channels are even more frequently observed outside the postsynaptic density, along the extrasynaptic membrane of spines, where they might associate with CaV channels or with other signalling molecules like group I mGlu receptors.

Related publications

García-Negredo G, Soto D, Llorente J, Morató X, Galenkamp KMO, Gómez-Soler M, Fernández-Dueñas V, Watanabe M, Adelman JP, Shigemoto R, Fukazawa Y, Luján R, Ciruela F (2014) Co-assembly and couplintg of SK2 and mGlu5 receptors. Journal of Neuroscience

Fajardo-Serrano A, Wydeven N, Young D, Watanabe M, Shigemoto R, Martemyanov KA, Wickman K, Luján R. (2013) Association of Rgs7/Gβ5 complexes with girk channels and GABAB receptors in hippocampal CA1 pyramidal neurons. Hippocampus 23(12):1231-45.

Huang Z, Luján R, Kadurin I, Uebele VN, Renger JJ, Dolphin AC, Shah MM. (2011) Presynaptic HCN1 channels regulate Cav3.2 activity and neurotransmission at select cortical synapses. Nature Neuroscience 14(4):478-86.

Ciruela F, Fernández-Dueñas V, Sahlholm K, Fernández-Alacid L, Nicolau JC, Watanabe M, Luján R. (2010) Evidence for oligomerization between GABA(B) receptors and GIRK channels containing the GIRK1 and GIRK3 subunits. European Journal of Neuroscience 32(8):1265-77.

Lin MT*, Luján R*, Watanabe M, Frerking M, Maylie J, Adelman JP. (2010) Coupled activity-dependent trafficking of synaptic SK2 channels and AMPA receptors. Journal of Neuroscience 30(35):11726-34.

Canela L, Luján R, Watanabe M, Lluís C, Mallol J, Canela EI, Franco R, Ciruela F. (2009) The association of metabotropic glutamate receptor type 5b with the Neuronal Ca2+-binding protein 2 modulates receptor function. Journal of Neurochemistry 111(2):555-67.