Boyd, David Frank; (2001) Potassium current regulation and intracellular calcium stores in rat cerebellar granule neurons. Doctoral thesis (Ph.D.), University College London.

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Abstract

Cerebellar granule neurons (CGNs) possess a standing outward potassium current (IKso) which shares many properties with the two-pore domain potassium channel TASK-1. This thesis extends the characterisation of IKso and considers its modulation by muscarinic M3 receptor activation concentrating, in particular, on the role of intracellular calcium. IKso was found to be permeable to other monovalent cations with a permeability sequence T1+ = Rb+ = K+ >> Cs+ > NH4+ > Li+. IKso was inhibited by muscarine (10?M; 70 ± 2%, n = 61) and histamine (30?M; 25.8 ± 7.3%, n = 6 out of 9). Muscarine (10?M) was only able to evoke a rise in intracellular calcium concentration ([Ca2+]i) in a small proportion of CGN (9%). The thapsigargin sensitive, intracellular calcium stores in CGN were found to be depleted at rest and this may underlie the lack of calcium response to muscarine. In this respect, a prior depolarisation with potassium, which is shown to load calcium stores, increased the size of the calcium response and the proportion of CGN responding to muscarine (to 51%). Raising [Ca2+]i with ionomycin (1?M) elicited a small decrease in IKso (14 ± 4%, n=7). Thus, elevations in [Ca2+]i do not appear to mediate muscarinic inhibition of IKso. Muscarinic inhibition of IKso was unaffected by the inhibitors of mitogen activated protein kinase kinase (MEK), PD 98059 and U 0126. While phorbol 12- myristate 13-acetate (PMA) had no effect on IKso amplitude, it did diminish muscarinic inhibition of IKso. Surprisingly, PD 98059 and U 0126 concentration dependently diminished IKso amplitude (at 30?M by 48 ± 1% (n = 10) and 46 ± 3% (n = 7), respectively) in a voltage insensitive manner. The mechanism of block by these compounds remains unknown but is not believed to be due to an action on MEK.

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