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Regulation of N type calcium channel expression, trafficking and modulation (360G-Wellcome-077883_Z_05_Z)

Voltage-gated calcium channels are essential to numerous aspects of the function of excitable cells. In neurons they are involved in the release of neurotransmitters, and in a number of other processes in which a rise in intracellular Ca2+ is the primary signal. Two very important neuronal subtypes of calcium channels are N-type (CaV2.2) and P/Q-type (CaV2.1), with the former being particularly important at peripheral synapses and neuro-effector junctions, in the autonomic and sensory nervous systems. In nociceptive dorsal root ganglion neurons they are a therapeutic target for anti-nociceptive drugs. The function of these voltage-gated calcium channels may be modulated by several means, for example their expression is controlled by the auxiliary ß as well as a2d subunits, and in the short term they are inhibited by the activation of G-proteins via a variety of G-protein coupled receptors. Over a number of years, my group has examined the properties of cloned calcium channels, expressed both in non-neuronal heterologous expression systems and in neurons. The key goals of the current proposed programme of work relate to four interlinked themes involving CaV2.2 calcium channels: (i) examination of CaV2.2 calcium channel mRNA trafficking and stability, since the mRNA for these channels has particular trafficking motifs in it, (ii) examination of CaV2.2 calcium channel protein trafficking and the role of the auxiliary ß subunits and (iii) study of the mechanism of G-protein modulation of plasma membrane CaV2.2 calcium channels. Finally (iv) we will study the pathophysiological consequences of mis-assembly of CaV2.2 calcium channels. The last theme could also generalise to CaV2.1 calcium channels and may relate to the calcium channelopathy, episodic ataxia-type 2, which is caused by mutations in this channel that are often truncating mutations

£1,375,208

20 Oct 2005

Grant details
Amount Awarded 1375208
Applicant Surname Dolphin
Approval Committee Neurosciences And Mental Health
Award Date 2005-10-20T00:00:00+00:00
Financial Year 2005/06
Grant Programme: Title Programme Grant
Internal ID 077883/Z/05/Z
Lead Applicant Prof Annette Dolphin
Planned Dates: End Date 2012-11-30T00:00:00+00:00
Planned Dates: Start Date 2006-12-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Greater London
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