Role of potassium channels in regulating neuronal activity
Year: 2007
Type: dissertation
Abstract: The firing behaviour of excitable cells is fundamental for the\ninformation processing in multicellular organisms, varying from single\nspikes to different forms of repetitive firing. Of the many regulators,\nvoltage gated potassium channels play a major role.\n\nIn this thesis some aspects of the potassium channel regulation of firing\nare explored. (i) The role of the channel density per se is studied in an\nin silico model, (ii) the effect of a spontaneously mutated potassium\nchannel is studied in hippocampal slices from a mouse model, (iii) the\neffect on the expression of potassium channels in general, and\nconsequently on the firing, by this spontaneous mutation is studied in\nXenopus oocytes, (iv) the molecular mechanisms giving the hERG channel\nits specific regulatory role in cardiac firing are studied in Xenopus\noocytes and (v) the mechanisms behind the spontaneous current events in\nhypothalamic neurons, shaping hypothalamic firing patterns, are studied\nin mechanically isolated cells.\n\nThe computational study was based on an analysis of a hippocampal\ninterneuron and showed that varying the density of sodium- and potassium\nchannels results in qualitatively different firing patterns and threshold\ndynamics, mathematically associated with different bifurcation types\n(saddle node, Hopf and double-orbit).\n\nThe study of the effects of a mutated potassium channel was performed on\na megencephalic mouse model, having a truncated KV1.1 channel gene\n(mceph). A patch-clamp analysis of neurons in hippocampal slices showed\nthat one effect of the truncation on the neurons was, in addition to an\nenlarged size, a slight increase in firing frequency, compatible with a\ndecreased density of potassium channels.\n\nThe study of the MCEPH expression in mceph/mceph mice, showed that it\nindeed was expressed, but completely retained in the ER. It was also\nfound that it retained other KV1 channels in the ER, reducing their\ndensity in the plasma membrane.\n\nThe study of the molecular mechanism underlying the specific features of\nhERG was performed by analysing Shaker channels with hERG emulating\nsubstitutions. hERG is structurally characterized by aromatic residues in\nthe internal vestibule. We introduced one of these, tyrosine, in Shaker,\nand found that it induced hERG like features, suggesting that the\ntyrosine residue has a role in forming the specific hERG kinetics. In\naddition, the tyrosine substitution induced an inactivation component\nwith inversed voltage-dependence.\n\nThe study of the spontaneous hypothalamic current events was performed\nwith medial preoptic area neurons and showed that the currents were due\nto calcium-activated potassium channels of the SK3 subtype, triggered by\nCa2+ release from intracellular stores via ryanodine receptor channels.\nCurrent clamp measurements showed that the spontaneous current events had\na role in shaping the firing patterns of the medial preoptic neurons.\n\nIn conclusion, this thesis work adds information on the role of potassium\nchannels in regulating neuronal firing at different levels. It suggests\nways to understand pharmacological effects on firing patterns, presents a\nbackground for future studies on the trafficking of potassium channels,\nsuggests a novel determinant involved in hERG kinetics and indicates a\nrole for SK channels in neuronal firing.
Source: Figshare
Author: G. Klement
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1752520456