RICERCA ITALIANA     

Neuronal sodium, calcium and potassium channels: physiological role and channelopaties

Università degli Studi di Torino

Abstract

Voltage-gated ion channels are membrane integral proteins activated by voltage, which allow the passage of Na, Ca, K and Cl ions across the cell. All animals, including humans, take profit of the ability of ion channels to open and conduct ions through the plasma membrane in both directions, generating action potentials that sustain cell excitability. Action potentials are crucial to control vital functions such as sensory transduction, muscle contraction, synaptic plasticity, learning and memory. Usually, all these functions require a relatively low number of channels, which is in all cases surprisingly lower with respect to the number of genes available in our genoma (more than 60 genes for K channels, 10 genes for Ca and 9 for Na channels). Understanding the structure and function of each ion channel has been, and remains, the “main challenge” of neuroscientists interested on this issue.

Besides that, exits a further order of complexity associated with: 1) the functioning of the protein structures forming the pore that are often interacting with other proteins (auxiliary subunits) regulating the degree of channel expression and functioning, 2) the action of several endogenous molecules and intracellular second messengers activated by specific membrane receptors interact with ion channels, modulating their activity, and 3) the increased degree of channel expression that can be induced by neuronal growth factors and external stimuli such as hypoxia. It is >>>

Principal Investigator

Emilio Carbone Università degli Studi di TORINO

Research Objectives

This project proposal for the years 2007-2009 is the logical prolongation of that previously proposed and funded for the period (1997-2007) (coordinated before by E. Wanke and more recently by E. Carbone) with the same five research Units and a common task focused on the functional role of neuronal voltage-gated ion channels and their channelopathies. The selection of the partners has been done in the previous PRIN to better focusing on the properties of Na, Ca and K channels of the central nervous system and to allow more effective exchanges of competence on different neuronal preparations (cultured neurons, monosynaptic preparations, neuronal networks and brain slices) and modern methodologies for recording neuronal activity. The unifying element of this project is the opportunity for the five Units of effectively collaborating by joining their own experience on different neuronal preparations and a number of complex methodologies that would be nearly impossible to develop by single University groups. This is important for the final outcome of the project, which is the more deep knowledge of the role of ion channels and the origin of channelopathies at various levels of cellular complexities: single neuron, neuronal networks and entire brain.

To give an idea of the main issues that will be investigated and their extreme broadness and homogeneity, we will list here the titles of the project of the five Units, while in the graphic scheme are reported the >>>

First Results

As mentioned before the main output of this national research project is the identification of the functional role that a number of Na, Ca and K channels play in the generation of important neuropathologies such as migraine, epilepsy, Alzheimer, psychiatric disorders and stress. There are, however, many distinct results that each Unit is expecting to attain from their tasks and given their specific relevance to the work of each group we will list below the main outcomes expect:

TORINO (Carbone): “FUNCTIONAL ROLE OF NEURONAL L- AND T-TYPE CALCIUM CHANNELS IN THE CONTROL OF PACEMAKER ACTIVITY AND NEUROSECRETION: IMPLICATIONS IN CHANNELOPATHIES AND ALTERED CONDITIONS OF NEURONAL EXCITABILITY”

Task #1 - Role of L-type channels in pace-making cells and neurotransmitter release in hippocampal neurons and chromaffin cells under normal and altered physiological conditions.
We expect to quantify the role that the L-type channels play in the pace maker activity and hormone release in mouse chromaffin cells and hippocampal neurons. In particular, we expect to identify whether the Cav1.3 channel isoform is the one more involved and whether its up- or down regulation by external modulators will be reflected in a change of action potential activity and exocytosis. We expect also to observe the increased level of L-type channels in NGF-treated hippocampal neurons and to estimate their possible involvement in the control of neurotransmitter release at >>>

Timescale

24 months

National and international background

Ion channels are protein structures that play a central role in the nervous system by conditioning neuronal maturation and development of neuropathologies. In the last twenty years there has been an incredible explosion of works focused on the molecular and functional identification of different classes of Na, Ca and K channels, so that, at the moment we count more than 60 types of K channels, 10 types of Ca channels and 9 types of Na channels, with specific structural and functional properties.

Many functions are known but most remain obscure such as: 1) the molecular bases of Na, Ca and K channel gating, 2) the role of different subtypes of Na and Ca channels supporting the pace-maker current of central neurons, 3) the contribution of newly recruited Na and Ca channels in lowering the threshold of action potential firing in various forms of hyperalgesia and epilepsy, and 4) the distribution and role of different presynaptic Ca channel types responsible for vesicles release. These are only few of the many examples of unsolved problems, relative to the functions of voltage-dependent ion channels. Besides this, we are facing now a new fascinating issue of clinical interest that involves an increasing number of pathologies strictly related to the structural mutations of ion channels (channelopathies) that are identified and classified on the bases of the type of mutated channels and associated pathology. The link between “function” and “dysfunction” is so tight >>>