Research

Tuning the Cell's Antenna

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Primary cilia are hair-like cell membrane protrusions supported by an internal scaffold called the axoneme, whose constituent microtubules emanate from the basal body, one of the centrioles of the cellular centrosome. As explained here, primary cilia work as cell type-specific antennae, and we study how cells tune these antennae so they can optimally sense their cognate signals.

One of the main receptor types operating in primary cilia are GPCRs (G protein-coupled receptors). For instance, our vision relies on GPCRs known as opsins that function inside the cilia of rods and cones, our retinal photoreceptor cells. We also smell through GPCRs known as odorant receptors or ORs. Inside our brains, many neurons use ciliary GPCRs to sense a variety of neuromodulators, molecules that affect neuron behavior and neural circuit output. Some of these neuromodulators include serotonin (5HT), somatostatin (SST), and melanin-concentrating hormone (MCH). One of our main lines of research in the lab aims to elucidate the detailed molecular mechanisms whereby specific 5HT (HTR6), SST (SSTR3) and MCH (MCHR1) receptors accumulate inside primary cilia. These ciliary receptors are involved in multiple diseases, including neuropsychiatric diseases (HTR6), brain tumors (SSTR3), obesity and sleep disorders (MCHR1), and ciliopathies like Bardet-Biedl syndrome (BBS). Since GPCRs, as a group, are the most common drug target in the human clinic, our studies on GPCR ciliary targeting have important biomedical implications.

We are also very interested in the ciliary targeting mechanisms and function of INPP5E, a phosphoinositide 5-phosphatase that plays a key role in controlling ciliary lipid composition, a major aspect of the tuning of the ciliary antenna. By affecting the ciliary levels of phosphoinositide lipids, INPP5E regulates processes such as axon pathfinding in the brain, Hedgehog signaling, or ciliary disassembly in response to growth factors. Mice lacking INPP5E die shortly before birth with defects in brain, eyes, skeleton and kidneys, among others. In humans, INPP5E mutations cause ciliopathies such as MORM and Joubert syndromes. Thus, like GPCRs, INPP5E is also biomedically important, and a potentially druggable target.   


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