Class D L-type Calcium channels: physiological role and therapeutic potential

Hertha Firnberg Position T 38 Class D L-Type Calcium Channels Martina J. SINNEGGER 29.06.1999 Drugs that selectively modulate the function of L-type Ca2+ channels in neurons and endocrine cells are considered promising new therapeutic tools for the treatment of type I and 11 diabetics, hearing disorders and aging-related decreases in brain function. Currently available L-type Ca2+ channel modulators, such as dihydropyridines (DHPs), cannot be exploited for this therapeutic goal because of their preferential action in the cardiovascular system in vivo. Therefore the potential therapeutic effects of L-type channel modulation in neurons and the endocrine system can only be assessed and exploited by developing a new generation of L-type channel modulators that selectively target L-type channels in endocrine tissues and lack cardiovascular effects. A rational basis for the development of such drugs is provided by the finding that L-type Ca2+ channel function in the cardiovascular system is mainly represented by so-called class C channels (containing a DHP-sensitive a 1C subunit), whereas in pancreatic ß-cells and e.g. sensory hair cells of the cochlea the class D isoform (containing a DHP-sensitive a 1D subunit) is the predominant form. Class D selective drugs could therefore represent such a new generation of neuronal and endocrine-selective drugs modulating Ca2+ influx and signal transduction in these cells without affecting the cardiovascular system. To test this hypothesis I will develop an animal model that can be used to assess the therapeutic potential of class D channel modulation in vivo without the need to develop class D selective drugs. This will be accomplished by targeted disruption of DHP sensitivity of class C channels in mice. The rationale is to introduce a targeted mutation into the mouse a 1C-gene thereby reducing high DHP sensitivity for channel blockers (e.g. isradipine) and activators (e.g. BAYK 8644). In homozygous mice class C channel complexes should display negligible DHP sensitivity and therefore DHP effects should be limited to class D Ca2+ channels. Thus in these mice currently available DHPs should act as class D - selective modulators. In vitro and in vivo analysis should allow to determine the extent of contribution of class D channels to signal transduction in the neuroendocrine system and to predict the therapeutic potential of selective class D channel modulators for the treatment of neuronal and endocrine dysfunction.