There are reasons why you should accept that pacemaker setting can be dependent on K

This new SA node compared with the newest ventricle expresses calcium sensitive adenylyl cyclase isoforms [ 105 ]

50 pS in contrast to the situation in the ventricle where it is closer to 70–80 pS [ 95 ]. _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 ]. 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 have explored this question in the mouse using cre\loxP technology [ 98 ]. We made use of a cre driver line that allows selective deletion of genes within the adult conduction system on the addition of tamoxifen [ 98 , 99 ]. The resulting knockout mice are labelled as cKO. We first isolated K_ATP currents in single SAN cells and find that only approximately half the cells contain currents [ 98 ]. This is not surprising given the heterogeneous electrophysiological nature of the SAN [ 100 ]. The pharmacology of the response is also interesting with diazoxide activating and tolbutamide inhibiting and this profile is more typical of SUR1 than SUR2 [ 101 ]. In murine atrial myocytes SUR1 underpins a significant population of K_ATP tinder for couples channels [ 102 ]. Furthermore when action potentials were measured in single SAN cells, there was delayed repolarisation in cKO cells resulting in prolonged cycle length [ 98 ].

The latest murine model along with allows the study of the during the-vivo psychological effects of your Kir6.step 1 removal [ 103 ]. Using inserted telemetry probes, i counted heartrate and you can ECG parameters when you look at the conscious mice more than a protracted several months. cKO rats is actually bradycardic and in some rats there were episodes of sinus arrest that have been perhaps not observed in littermate control [ 98 ]. Also, there clearly was an indication of atrioventricular nodal breakdown that have a growth of the Publicity period into ECG [ 98 ]. We together with noticed certain more compact pathological alter that have fibrosis regarding the SA node in a number of of the cKO mice [ 98 ]. The phenotype is not as pronounced as in the worldwide Kir6.step 1 knockout animal although handicap away from vascular reactivity and you may lack away from protective answers years [ 93 , 98 ].

Notably this level of cells are significantly reduced in cKO mice [ 98 ]

In summary, our recent studies show that K_ATP channels are constitutively active in SA nodal cells. The current seems to influence repolarisation predominantly and this results in an increased cycle length. In-vivo this leads to bradycardia but there was also evidence of sinus pauses, heart block and pathological changes in the SA node [ 98 ]. It is surprising that there are no effects on the maximum diastolic membrane potential. Kir6.1 is a member of the inwardly rectifying family of potassium channel however the currents are more outwardly rectifying [ 98 ]. Additionally, it is plausible that there may be some cyclical regulation of K_ATP channel activity during repolarisation perhaps by calcium and\or cAMP and protein kinase A to explain this paradox. Signalling via cAMP seems to be significantly adapted in the SA node. Adenylyl cyclase is constitutively active and this leads to basal protein kinase A activation [ 104 ]. PKA activity, and also that of calcium calmodulin dependent kinase II, is necessary for normal pacemaking as inhibitors of these kinases lead to significant slowing of beating [ 25 , 106 ]. Given the sensitivity of both adenylyl cyclase and calcium calmodulin dependent protein kinase II to calcium there may also be cyclical variations in activity that, in addition to phosphorylating phospholamban, may also phosphorylate K_ATP channels. On the background of high phosphatase activity this may lead to variations in beat-to-beat channel activity and account for the prominence of currents during repolarisation. 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 ].