Coupling between receptors, ion channels and other signalling molecules

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) GABA_B receptors and effector ion channels: GABA_B 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 Ca_²⁺-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.