Use of peptide fragments for modulating calcium channels, e.g. for identifying agents for treating epilepsy, derived from specific loops in the channel alpha subunit

摘要

Use of peptide fragments (I) based on the alpha 1-subunit of mammalian calcium channels (CC) to screen for agents (A) that modulate numbers and/or inactivation of CC, is new. Use of peptide fragments (I) to screen for agents (A) that (i) restore to normal the number of calcium channels (CC) in a cell membrane (CM) where this is abnormally reduced or increased; (ii) increase the number of CC in CM; (iii) reduce the number of CC in CM and/or (iv) regulate the inactivated state of neuronal CC implicated in release of neurotransmitters. (I) (i) corresponds to loops I-II and/or III-IV of the alpha -subunit, or their derivatives formed particularly by substitution, deletion and/or addition of at least one amino acid (aa), or their derivatives, especially with a peptide component of at least 5 aa, where those derived from the I-II loop bind to the beta -subunit or III-IV loop and those derived from the III-IV loop bind to the I-II loop. Alternatively (I) (i) corresponds to mutant forms with one or more aa changes where the mutations involve aa essential for expression of CC at the surface of the membrane. (I) may be replaced by cells transformed by nucleic acid that encodes these peptides. Independent claims are also included for the following: (1) screening (M1) using (I); and (2) mutant forms of the I-II loop of the human or rabbit calcium channel (Cav2.1) alpha 1-subunit.