Metabolic changes and Cav1.2 protein expression - is Rad the missing link?

Fabisch, Christian. Herzig S. Department of Phamacology, Gleueler 24, 50931 Cologne, Germany.

Diabetic cardiomyopathy is regarded as an entity characterized by impaired contractile function in the absence of coronary artery disease and hypertension. In hearts of obese type 2 diabetic mice (db/db mice showing a leptin-receptor dysfunction) we found decreased ventricular expression of the L-type Ca2+ channel pore protein Cav1.2, reduced whole-cell calcium current density, and unchanged single-channel activity (Pereira et al.).
Interestingly we found no changes of Cav1.2 expression nor modulated whole-cell Ca2+ currents in ob/ob mice (expressing a dysfunctional leptin) the apparently most similar mouse model compared to db/db. Recent data suggest that members of the RGK protein family are potential modulators of membrane targeting of voltage-dependent Ca2+ channels (Corell et al.). Rad (Rad associated with diabetes) is a favoured candidate, since it is located in cardiac muscle and known to inhibit L-type Ca2+-current and expression of Cav1.2 protein in guinea pig ventricular myocytes (Yada et al.). We currently investigate protein levels of Rad-expression and a putative correlation with expression of Cav1.2 in mice showing diverse metabolic phenotypes common for diabetes: 1. wildtype mice on high fat diet, 2. mice showing a leptin-receptor dysfunction (db/db), 3. mice expressing a dysfunctional leptin (ob/ob), 4. mice lacking insulin receptor substrate 2 (IRS2-/-), 5. mice lacking the insulin receptor in skeletal muscle (MIRKO) and 6. mice with streptozotocin induced diabetes type 1.

Western Blot data show a significant positive correlation of Rad- vs. Cav1.2-expression across all investigated mouse models. Since these findings are in apparent contradiction to recent data of Yada et al. it might indeed reflect a typical feature of diabetic cardiomyopathy and preliminary stages.

Pereira L, Matthes J, Schuster S, Valdivia HH, Herzig S, Richards S, Goméz AM. Diabetes 2006 Mar; 55:608-15.
Correll RN, Pang C, Niedowicz DM, Finlin BS, Andres DA. Cell Signal. 2008;20(2):292-300.
Yada H, Murata M, Shimoda K, Yuasa S, Kawaguchi H, Ieda M, Adachi T, Murata M, Ogawa S, Fukuda K. Circ Res. 2007 Jul 6;101(1):69-77.