On the Potential Interaction between Non-Selective Cation Channel TRPM4 and the Sulfonylurea Receptor SUR1

Abstract

The sulfonylurea receptor SUR1, of the ABC protein superfamily, associates with inward-rectifying K channel subunits Kir6.2 or Kir6.1 to form KATP channels, which link metabolism to electrical activity in multiple cell types. The strong coupling of SUR1 with Kir6 appears exclusive, but recent studies argue that SUR1 also associates with and regulates TRPM4, of the transient receptor potential (TRP) channel family of non-selective cation (NSC) channels. It has been reported that, following stroke, brain or spinal cord trauma, SUR1 is expressed de novo in neurovascular cells at the injury site. In these cells, there appears to be dramatic upregulation of a NSC conductance with TRPM4-like properties, which seems to be reduced by sulfonylureas and enhanced in presence of the KATP channel opener diazoxide, leading to the postulation that post-traumatic NSC currents are determined by SUR1-modulated TRPM4 channels (Simard et al., J Neurosurg 113: 622-9; 2010). However, direct evidence for functional association of TRPM4 and SUR1 is lacking. To address this, we performed inside-out membrane patch-clamp of COSm6 cells expressing TRPM4 channels with or without SUR1. TRPM4-mediated, non-selective currents were Ca2+-activated, voltage-dependent, underwent desensitization, and were inhibited by ATP, but were insensitive to diazoxide, glibenclamide and tolbutamide. These properties were not affected by co-transfection with SUR1 albeit functional, sulfonylurea-sensitive KATP channels were formed when the same SUR1 was co-transfected with Kir6.2. In cells co-transfected with Kir6.2, SUR1 and TRPM4, we measured Ca2+-independent, KATP-mediated K+ currents and Ca2+-activated, sulfonylurea-insensitive Na+ currents in the same patch, further showing that SUR1 subunits control KATP channel activity, without affecting TRPM4 channel properties. Co-transfection of TRPM4 and SUR1 does not elicit sulfonylurea-sensitive NSC currents as reported in stroke and brain injury models, suggesting that functional association of TRPM4 and SUR1 is unlikely.