The ATP-Sensitive Potassium Channel Subunit, Kir6.1, in Vascular Smooth Muscle Plays a Major Role in Blood Pressure Control

Abstract

A TP-sensitive potassium channels (K ATP ) are widely expressed in a range of tissues, including brain, heart, pancreas, and smooth muscle (SM), where they are involved in the regulation of biological processes such as insulin release, vascular tone, and adaptation to stresses such as ischemia and hypoxia. They are activated by either declining ATP or increasing ADP concentrations or both, thus coupling intracellular metabolism to membrane excitability. 1 K ATP channels are composed of 4 pore-forming Kir6.x subunits (Kir6.1 or Kir6.2) and 4 large regulatory sulphonylurea receptor subunits (SUR1, SUR2A or SUR2B) to form a functional hetero-octomeric complex.1 The vascular SM K ATP channel is thought to be composed of the Kir6.1 and SUR2B subunits.2,3 These SM K ATP channels have been implicated in the regulation of vascular tone through their proposed involvement in the actions of vasoconstrictors and vasodilators. [4][5][6][7] The integrative physiological role of these channels has been investigated in mice with global genetic deletion of either Kir6.1 or SUR2. 8,9 The mice were hypertensive and prone to sudden death, which was attributed to coronary artery vasospasm because of the absence of K ATP currents in the SM of the coronary arteries. However, when SUR2B was specifically expressed in SM in SUR2 global knockout mice resulting in reconstitution of the K ATP current, the lethal phenotype persisted.10 Furthermore, transgenic expression of SUR2A in cardiomyocytes in SUR2 null mice led to a dramatic reduction in the degree and frequency of episodes of ST elevation on the ECG measured using telemetry.11 The implication was that reconstitution of K ATP in cardiac myocytes led to a reduction of coronary artery SM spasm and it was proposed that K ATP channels outside the SM cell (SMC) are critical in driving the vascular phenotype in the global knockout mice and that the vascular SM K ATP channel contributes modestly to vascular control. 10 A global genetic deletion of Kir6.1 or SUR2 is not selective for the SM channel and potentially channels in the endothelium, nervous system, and heart might all be affected. Here, using a new mouse model, we show that Kir6.1 is indeed the pore-forming subunit of the K ATP channel in vascular SM and that it has a central role in the regulation of blood pressure (BP).Abstract-ATP-sensitive potassium channels (K ATP ) regulate a range of biological activities by coupling membrane excitability to the cellular metabolic state. In particular, it has been proposed that K ATP channels and specifically, the channel subunits Kir6.1 and SUR2B, play an important role in the regulation of vascular tone. However, recent experiments have suggested that K ATP channels outside the vascular smooth muscle compartment are the key determinant of the observed behavior. Thus, we address the importance of the vascular smooth muscle K ATP channel, using a novel murine model in which it is possible to conditionally delete the Kir6.1 subunit.

Potassium channels in the sinoatrial node and their role in heart rate control

“…In addition, ATP seems less potent in causing channel inhibition [90,91]. This current is recapitulated in heterologous expression systems by the co-expression of Kir6.1 and SUR2B [92] and smooth selective deletion of Kir6.1 (kcnj8) in mice abolished the current present in isolated single smooth muscle cells [93]. …”

“…There are reasons to believe that pacemaker function may also be influenced by K ATP channels containing the Kir6.1 subunit. Mice with global genetic deletion of Kir6.1 develop SAN failure and also heart block which leads to sudden death [93,96]. In our own studies we have studied mice with selective deletion of Kir6.1 in vascular smooth muscle or endothelium [93,97].…”

“…Mice with global genetic deletion of Kir6.1 develop SAN failure and also heart block which leads to sudden death [93,96]. In our own studies we have studied mice with selective deletion of Kir6.1 in vascular smooth muscle or endothelium [93,97]. These mice do not show the rhythm disturbance even with provocations that might provoke vasospasm and suggest by exclusion a potential role for Kir6.1 in the SA and atrioventricular node [93,97].…”

“…We also saw some modest pathological changes with fibrosis in the SA node in a few of the cKO mice [98]. The phenotype is not as pronounced as in the global Kir6.1 knockout animal but the impairment of vascular reactivity and lack of protective responses may accelerate pathological damage [93,98]. …”

“…It is also known that K ATP channels can be regulated by calcineurin [107,108]. It is known that Kir6.1-containing channels are prominently regulated by hormonal pathways and protein kinases both in heterologous and native tissues [93,109,110]. …”