Cell Calcium Extrusion Systems and their Role in Epileptogenesis

The precise control for maintenance of a normal intracellular calcium concentration in eukaryote cells is ac- complished by several systems located at the plasma membrane, as well as several internal membrane systems. Neurons are especially sensitive to changes in these control systems, since when fail and calcium homeostasis disturbed, the cell's metabolism is immediately modified and a pathological condition emerges. Such a condition has been associated with epi- leptogenesis, and especially to those mechanisms associated to calcium entrance or ON mechanisms. On the other hand, calcium extrusion mechanisms or OFF mechanisms, have been investigated to a lesser extent and therefore remain much less understood. Here, we present a review of these calcium extrusion systems located at the plasma membrane considered to be critical in the process of epileptogenesis; first of all the plasma membrane calcium ATPase (PMCA) as the catalytic moiety of the enzyme that moves calcium outwards in an energy-dependent fashion, and the Na + /Ca 2+ exchanger (NCX) coupled to the (Na + /K + )-ATPase. Based on present knowledge considering the wide range of isoforms found for PMCA and NCX and their specific kinetic characteristics, a hypothesis for their participation on the OFF mechanisms related to the genesis of epilepsy is discussed. Epilepsy can be defined as a chronic illness of diverse etiology characterized by recurrent crises due to an excessive and synchronic burden of cerebral neurons, eventually asso- ciated with diverse clinical and paraclinical manifestations. Epilepsy is a common pathology; World Health Organiza- tion (WHO) statistics revealed in the year of 2001 a preva- lence of 8.2 per 1,000 individuals in developed countries and 10 per 1,000 in developing countries. During the same year, incidence in developed countries was 50 per 100,000 indi- viduals in the general population, and 100 per 100,000 in developing countries. The analysis we have performed in the present study is related to the 50% of these patients that pre- sent by diverse external causes an acquired epilepsy (1). One very important period of epilepsy comprises epileptogenesis, i.e., the period in which epilepsy is developed, which can be considered the period between the lesion and the appearance of clinical manifestations. Epileptogenesis includes all phe- nomena that induce normal cells to discharge abnormally, which when repeated in a continuous fashion, produce an epileptic focus. For these phenomena to be expressed in cells, a change is required in the majority of systems control- ling neuronal excitability and inhibitory processes. Such phenomena allow an exaggerated abnormal discharge of neurons provoking hyperexcitability in the long term. During the period of epileptogenesis, there also appear aberrant in- terconnections that promote neuronal synchronization with the consequent clinical manifestations (1).