L-type calcium channels (LTCCs) play important roles in regulating cardiac physiology and appropriate trafficking of LTCCs to and density at the cell surface is necessary for cardiac inotropism and rhythmicity. Factors influencing the expression, half-life, subcellular trafficking, and gating of LTCCs are therefore critically involved in heart physiology and disease. Here, we investigated the molecular mechanisms through which the LTCC Cavβ2 chaperone regulates LTCC density by generating a mimetic peptide (MP) that directly targets Cavβ2 and affects, via multiple levels of regulation, Cavβ2 subcellular relocalization and function and subsequently LTCC density. The therapeutic potential of MP was assessed in mouse models of failing heart and cells expressing LTCC loss-of-function mutations associated with Brugada Syndrome, whereby MP recovers calcium handling. Thus, we provide proof-of-concept for the use of MP as novel therapeutic tool for the treatment of cardiovascular diseases through a mechanistically new direct regulation of the LTCC trafficking and life-cycle.
|Titolo:||Peptidomimetic Targeting of Cavβ2 Overcomes Dysregulation of the L-Type Calcium Channel Density and Recovers Cardiac Function|
|Data di pubblicazione:||2016|
|Appare nelle tipologie:||1.1 Articolo in rivista|