Repolarising currents
The major repolarising currents in ventricular myocytes are IKr and IKs and both components are also present in SAN myocytes [ 9 , 61 ]. IKr is named as such because it is rapidly activating and the currents are characteristically inwardly rectifying due to its unique inactivation properties [ 62 ]. IKr is composed of hERG (human ether-a-go-go related gene) and possibly a ? subunit of the KCNE family though this is still controversial [ 63 , 64 ]. IKr is an important current in SAN cells [ 65 , 66 ]. For example, the inhibitor E-4031 leads to significant perturbation of the SAN action potential and dofetilide (another blocker) slows pacemaking [ 61 ]. In contrast, IKs is characteristically activates slowly and the channel complex is formed by KCNQ1 (Kv7.1) and the ? subunit KCNE1 [ 67 , 68 ]. There may be some species differences in the relative magnitudes of IKr and IKs but IKs is also clearly present in the SAN [ 69 , 70 ]. One key property of these currents, in particular IKs, is the augmentation by ? adrenergic signalling: it is key in shortening the action potential duration during high heart rates [ 70 , 71 ]. Activation of ? receptors leads to PKA stimulation and direct phosphorylation of residues S27 and S92 in the channel N-terminus [ 72 ]. The increase in current requires KCNQ1 to be associated with KCNE1and is dependent on a protein kinase A anchoring protein (AKAP) yotiao\AKAP9 [ 72 , 73 ]. Unlike IKs regulation, there is no agreement on whether IKr currents can be increased by ? adrenoreceptor modulation [ 74 , 75 ]. Uniquely in the SAN, calcium-calmodulin kinase II may activate IKs and intriguingly this could affect calcium handling and channel modulation too [ 76 ].
Records potassium currents carried because of the twin pore channels are difficult to help you check out the considering its terrible pharmacology. Thus it looks likely that TREK1 plus leads to repolarisation.
However a recent study having fun with cardiac-specific TREK1 knockout mice revealed that this type of rats have been bradycardic and you can predisposed in order to sinus arrest [ 77 ]
ATP-sensitive potassium streams are widely delivered regarding cardiovascular system. As a whole the main focus have largely come towards the avenues within the fresh ventricle but characteristic currents normally filed regarding the atria and in the latest conduction system such as the SAN [ 78 , 79 ]. The fresh new identifying possessions ones avenues is their sensitiveness in order to intracellular nucleotides and tend to be triggered by the declining ATP accounts and you can\otherwise expanding magnesium ADP levels. The brand new route advanced is made up of five pore-forming inwardly-fixing Kir6.0 subunits (Kir6.step one, Kir6.2) including five regulating sulphonylurea receptors (SUR1, SUR2A, SUR2B) [ 80 – 82 ]. We have now know this type of channels better just like the unit computers underpinned from the thorough mutagenesis performs and more recently by the structural education. Cryo-electron microscopy shows how ATP binds with the pore-building subunit and how MgADP communicates High Point NC chicas escort towards the nucleotide joining domains about sulphonylurea receptor [ 83 – 85 ]. Despite the initially description of these streams about cardio [ 86 ] you may still find issues about their real emotional character. Kir6.dos is believed to help you underlie the fresh new classic most recent present in pancreatic ? structure and you can ventricular cardiomyocytes [ 87 ]. Kir6.2 international knockout mice are unable to endure high intensity take action partially because of impaired cardiac show [ 88 ].
There has been comparatively less work on the Kir6.1 subunit though it has been known since it was first cloned that it is widely expressed [ 89 ]. Furthermore, there exists, particularly in smooth muscle, a KATP channel with a lower single-channel conductance (35 pS vs 70 pS) with an absolute dependence on cellular nucleotide diphosphates for channel opening. In some papers this led to the channel being called a “KNDP” [ 90 ]. 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 ].