New nucleic acid encoding the non-selective cation channel OTRPC4, useful for treating osmolality-associated disorders, e.g. diabetes comprises the modulation of activity

摘要

Nucleic acid (I), comprising: (i) encodes the non-selective cation channel OTRPC4 or its fragments, functional or allelic variants or subunits; (ii) is a variant of (i) within the degeneracy of the genetic code; or (iii) hybridizes to (i). is new Independent claims are also included for the following: (a) nucleic acid (Ia) the hybridizes to (I) under stringent conditions; (b) recombinant vector containing (I) or (Ia); (c) host cell containing the vector of (b); (d) polypeptide (II) encoded by (I) or (Ia), or its fragments, variants, subunits, chemical derivatives, fusion proteins or glycosylation variants; (e) preparing (II) comprises culturing hosts of (c); (f) antibodies (Ab) specific for (II); (g) preparation of Ab by recombinant expression; (h) identifying blockers, activators or modulators of OTRPC4 by incubating cells of (c) with a test compound; (i) activator, blocker or modulator (A) of OTRPC4 identified by method (h); (j) antisense nucleic acid (Ib) that hybridizes to a part of (I) or (Ia) under stringent conditions; (k) (l) pharmaceutical composition containing (I), (Ia), (Ib), (II), the vector of (b) or the hosts of (c), plus carrier and auxiliary; (l) non-human mammal that includes (I) or (Ia) as a transgene in the genome; (m) non-human animal in which the genomic (I) or (Ia) sequences is inactivated or modified; and (n) methods for preparing animals of (m) and (l). - ACTIVITY : Antidiabetic; antihyperlipemic; antihyperproteinemic; antihypertensive; cerebral; renal. - MECHANISM OF ACTION : Activity modulator. Modulating activity of OTRPC4, a non-selective cation channel that is regulated by changes in osmolarity of the extracellular medium, i.e. it is an osmo-sensor for regulating cell volume. It is stimulated (inhibited) by a reduction (increase) in osmolarity and is permeable for all cations, but with a preference for calcium. HEK293 cells were transfected with a plasmid that expressed cDNA for OTRPC4, and the Fura-2 method used to measure intracellular calcium ion concentrations ([Ca]). For transfected cells, [Ca] increased from about 100 to 900 nM when the external osmolarity was reduced to 200 mOsmo/l and a subsequent increase in osmolarity caused [Ca] to decline to basal levels. The [Ca] for non-transfected cells was not altered by these changes. The transfected cells respond very quickly, within 30 sec. OTRPC4 was inhibited by lanthanum but not (up to 1 mM) by gadolinium.