Gallasch, L; (2015) Role of the heterotrimeric protein Gq and small GTPase RhoA in the cholinergic modulation of the slow afterhyperpolarizing current, sIAHP, in hippocampal pyramidal neurons. Doctoral thesis , UCL (University College London).

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Abstract

The network activity of the hippocampal formation underlying learning and memory processes is regulated by a number of ionic conductances that determine the neuronal excitability and firing patterns of hippocampal pyramidal neurons. The slow Ca2+-activated K+ current (sIAHP) and its modulation by acetylcholine (ACh) and glutamate play a crucial role in shaping these intrinsic properties of hippocampal pyramidal neurons. sIAHP follows a train of action potentials and is characterised by its dependency on the rise of intracellular Ca2+ and its slow time course, displaying activation kinetics of hundreds of milliseconds and decaying over seconds. It is responsible for spike frequency adaptation that restricts repetitive firing in response to a prolonged stimulus. Hence the suppression of sIAHP by ACh and glutamate, through metabotropic receptors, leads to an enhanced excitability of hippocampal pyramidal neurons. The underlying signal transduction cascade used by ACh and glutamate to inhibit sIAHP is not fully characterised, involving the G-protein subunit Gαq, but not its classical signalling pathway via phospholipase C β (PLCβ) (Krause et al., 2002). Employing molecular biology and imaging techniques in heterologous expression systems this study establishes that the small GTPase RhoA acts as a signalling partner of Gαq, pointing to an involvement of both proteins in a common signalling pathway that mediates the suppression of sIAHP upon the stimulation of G-protein coupled receptors (GPCRs) by cholinergic agonists in hippocampal pyramidal neurons. The introduction of activated and inactivated RhoA mutants into hippocampal pyramidal neurons by viral infection, and subsequent whole-cell patch clamp electrophysiology, showed that constitutively active RhoA-V14 reduces sIAHP significantly, mimicking the inhibitory effect of ACh, whereas sIAHP is unaffected in neurons expressing inactive RhoA-N19. An involvement of RhoA in the regulation of membrane excitability of hippocampal pyramidal neurons and thus in the shaping of neuronal activity on a relatively fast time-scale is a novel function for the small GTPase.

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