Pharmacological Approaches For Targeting Cardiovascular And Skeletal Muscle Katp Channelopathies

The pathological consequences of ATP-sensitive potassium (KATP) channel dysfunction in the cardiovascular system and skeletal muscle have recently been illuminated by the identification of two syndromic channelopathies, Cantu Syndrome and ABCC9-related intellectual disability and myopathy syndrome (AIMS). CS, which leads to low blood pressure and cardiac hypertrophy, arises due to gain-of-function mutations in KCNJ8 and ABCC9, which encode the Kir6.1 and SUR2 KATP channel subunits, respectively. Conversely, a splice-site mutation in ABCC9 (c.1320+1G>A), which results in the in-frame deletion of 52 amino acids encoded by exon 8 in SUR2 and consequent complete loss-of-function of KATP channels, has recently been identified in six patients with AIMS, characterized by skeletal muscle fatigability (Smeland et al. 2019, Nat Comm, 10:4457). Clinically used sulfonylurea KATP inhibitors, such as glibenclamide, represent a potential therapy for CS. Chronic glibenclamide administration in Cantu mice models which harbour CS-associated SUR2[A478V] and Kir6.1[V65M] mutations, administered via slow release pellets, results in normalization of BP and heart size in heterozygous SUR2[A478V] mice. Preliminary data suggest that the effect on heterozygous Kir6.1[V65M] mice is less pronounced, which likely reflects the decreased sensitivity of Kir6.1[V65M] containing channels to glibenclamide inhibition imparted by the biophysical effects of the mutation. Targeting KATP loss-of-function in AIMS poses a distinct challenge, how to fix a channel which is not there? KATP LoF in vascular, cardiac, and skeletal muscle is associated with increased intracellular calcium levels, and thus we hypothesized that a calcium channel blocker (verapamil) may normalize BP and reverse skeletal muscle fatigability observed in AIMS. However, we report the unexpected finding that verapamil induces sudden death in SUR2-STOP mice, in which functional myocyte KATP channels are absent. Ongoing studies seek to understand the underlying basis, and to identify viable therapies for CS and AIMS.