Functional dynamics of ion channels and signaling activity of neurons Magura I.S. Institute of Physiology NAS Ukraine

Complex processing and integration of the signals observed in neurons are facilitated by a diverse range of the gating properties of the ion channels in this cell type, particularly of the voltage – gated K+ channels (Kv). A distinctive combination the of ion channels endows neurons with a broad repertoire of the excitable properties and allows each neuron to respond in a specific manner to a given input at a given time (Bezanilla 2008; Bean 2007; Debanne 2009; Li at all 2006) The information contained in spike timing is available immediately, rather than after an averaging period. Furthermore, the timing of patterns of spikes can potentially transmit even more information than the timing of the individual constituent spikes. Ion channels are not only crucial in healthy individuals, but several of them have been implicated in disease, either genetic or acute. The possible treatments to channel associated disease will be accelerated if we understand in detail how channels are implicated in the physiology of the cell and if we could design modifications that restore normal function/ for example several human genetic diseases, such as pathologies involving cardiac arrhythmias, deafness, epilepsy, diabetes, and misregulation of blood pressure, are caused by disruption of K channel genes. Introduction

Extracellular K+ specifically modulates a PC – 12 K+ channels Elevation of [K ]o may occur just through high levels of neuronal activity and through specific actions of neurotransmitters on glial cell. Variations in [K ]o have been implicated in pathogenic of several disorders, such as epileptyform seizures and electrical instability of the heart following acute ischemia.

DIVERSITY AND DYNAMICS OF THE SIGNALING FUNCTION OF THE DENDRITES FUNCTIONAL DINAMICS OF ION CHANNELS AND SIGNALING ACTIVITY OF NEURONS

Kv channel in a macromolecular complex. A model of a single Kv channel with multiple accessory subunits and interacting proteins as discussed in the text. This is a hypothe tical situation for illustration because not all subunits and proteins may necessarily coexist within the same complex. Only two subuni ts each of Kvβ and KchIP are shown, though their stoichiometry is four-fold. Only one KCNE subunit is shown. Inactivation particles are shown approaching the cytoplasmic pore from both the α-subunit T1 domain (blue) and the Kvβ subunit (green). An A-kinase anchoring protein (AKAP) is shown as a scaffold for protein kinase A (PKA), a protein phosphatase (PP), the channel, and a G-protein coupled receptor.

LOCALIZATION OF K CHANNELS TO LIPID RAFTS K+ channels targeting and cellular localization were believed to involve primarily protein-protein interactions. However, there is increasing interest in the potential role for cellular lipids in the regulation of channel localization. Lipid rafts are specialized membrane micro domains that are rich in sphingolipids and cholesterol. These rafts have been implicated in the organization of many membrane-associated signaling pathways. Biochemical and functional evidence indicate that Kv channels, in addition to other ion channels, localize to lipid raft microdomains on the cell surface (Martens et al., 2004).

FUNCTIONAL DINAMICS OF POTASSIUM CHANNELS Effects of [K+] 0 on the potassium current

FUNCTIONAL DINAMICS OF POTASSIUM CHANNELS Influence of external potassium ions on potential gating processes (HH models) Influence of external potassium ions on the potential dependence of the normalized potassium conductance

FUNCTIONAL DINAMICS OF POTASSIUM CHANNELS Voltage clamp registrations of potassium currents in barium solution and inactivation kinetics (semi Lg scale), (interval 2 s)

Effects of external Ba2+ on the plasticity of action potentials repetitive firing (current clamp, interval 3 s). Barium size allows it to sit into the selectivity filter, but its charge apparently causes it to bind too FUNCTIONAL DINAMICS OF ION CHANNELS AND SIGNALING ACTIVITY OF NEURONS

Effects of external TEA (8mM/L) on the functional dynamics of actions potential generation FUNCTIONAL DINAMICS OF ION CHANNELS AND SIGNALING ACTIVITY OF NEURONS

Phase plane plot. Information about the time course of the spike is lost, but some aspects of the spike are clearer than in a simple display voltage versus time.

FUNCTIONAL DINAMICS OF ION CHANNELS AND SIGNALING ACTIVITY OF NEURONS Action potential (Planorbis corneus) during repetitive firing. Upper trace, membrane potential, lower traces, rate of change of potential. (a) Action potentials and their first derivatives superimposed during repetitive firing. (b) A precise control of neuronal action potential patterns (phase plane plot).

FUNCTIONAL DINAMICS OF ION CHANNELS AND SIGNALING ACTIVITY OF NEURONS Action potential (Limnea stagnalis) during repetitive firing. Upper trace, membrane potential, lower traces, rate of change of potential.

Depolarization effects on the neuronal action potential (Planorbis corneus) FUNCTIONAL DINAMICS OF ION CHANNELS AND SIGNALING ACTIVITY OF NEURONS

New dimensions of neuronal plasticity

GLIAL FUNCTION

Conclusions The main function of the nervous system should be qualified as integration. This process allows the organism to estimate and compare various aspects of information coming to the nervous system and to form the corresponding adequate decisions. Single events of integrative activity of the brain are realized in separate neurons. Recent evidence indicates that the neuronal message is persistently filtered through regulation of voltage–gated ion channels. Mammalian central neurons typically express more than 50 different types of voltage-dependent ion channels. Potassium channels are the most diverse class of ion channels, and are important for regulating neuronal excitability and signaling activity in variety of ways. They are major determinants of membrane excitability, influencing the resting potential of membranes, wave forms and frequencies of action potentials, and thresholds of excitation. It is clear that the impact of ion channel research on our understanding of the neurons system is only starting. Ion channels fulfill important function in many signal transduction pathways. Neurons transmit information by transforming continuously varying input signals into trains of discrete action potentials. The coding scheme used in this process is an unresolved issue that is critical to computational theories of brain function. Ion channels are not only crucial in healthy individuals, but several of them have been implicated in disease, either genetic or acute. The signal function of the neurons is characterized by a highest form of plasticity, namely methaplasticitly. Recent evidence indicates that the neuronal message is persistently filtered through regulation of voltage–gated ion channels