In the lung, Ca2+ ion plays a crucial role in different functions. It participates in the contraction of airways smooth muscle, in mucus and electrolyte secretion, in the defence mechanisms associated to the ciliary activity and in the activation of many cells involved in the inflammatory response. Intracellular Ca2+ levels are controlled by several transport mechanisms, located to both the plasma membrane (e.g., TRP channels) and intracellular organelles (e.g., the SERCA pumps in the endoplasmic reticulum, ER). We tackle the molecular mechanisms generating Ca2+ signals, the identification of genetic defects in channels ("channelopathies") and other Ca2+ transport mechanisms associated to common chronic respiratory diseases and the functional consequences that may arise from the altered proteins.
Hypertension is one of the most important predictors of cardiovascular diseases such as coronary heart disease (CHD) and stroke. Despite its social and clinical importance, the vast majority of the cases are of unknown origin, being classified as essential hypertension. Essential hypertension is characterized by an increase in total peripheral resistance (reduction of the diameter of small arteries and arterioles), which, in turn, is governed by the contractile state of the vascular smooth muscle (VSM). We aim to study different ion channels and receptors involved in the initiation and maintenance of the contractile state of the VSM. The HERACLES network (http://www.redheracles.net/) has two major objectives, (1) the identification and regulation of molecules relevant to the control of the vascular tone, and (2) the search for genetic alterations in those molecules that might serve as markers of hypertension and CHD. The final goal is the improvement of public health, i.e., identification of risk factors, development of diagnostic kits and therapeutic molecules.
Voltage-dependent Ca2+ channels is involved in multiple cell functions, including the control of neuronal excitability and neurotransmitter release, where other ion channels and pumps also play a key role. Among the different voltage-dependent Ca2+ channels, the P/Q-type is essential for neurotransmission through the central nervous system. Mutations in the gene encoding the P/Q-type Ca2+ channel a subunit (a1A), CACNA1A, are linked to inherited paroxystic neurological diseases such as familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, and might be the cause of more common forms of migraine with and without aura. These mutations affect P/Q channel function, occasionally depending on the presence of a particular regulatory b subunit isoform. However, because of the variability in the ways that those mutations influence P/Q channel function, along with the interaction of the a1A subunit with multiple regulatory proteins, the molecular and cellular events underlying the pathophysiology of these neurological disorders and its phenotypic diversity, are largely unknown. We aim to characterize new molecular and cellular mechanisms lying beneath the pathogenesis of these neurological disorders, with special focus on migraine and episodic ataxia, and to the identification of new targets for the development of future therapy.
One of the the main objectives of our project is the study of the mechanisms involved in the production of amyloid ß-peptide (Aß) in Alzheimer’s Disease (AD). Oxidative stress produces an increase in the amyloidogenic cleavage of the amyloid precursor protein (APP) by a direct effect of radical oxigen species (ROS).The other main objective of this project is the study of pathophysiological mechanisms triggering the Aß-mediated neurotoxicity. Aß-produced free radicals damage cell’s macromolecules and activate intracellular signalling that finally results in neuronal cell death.