Considering these characteristics from SAN electrophysiology, the opening away from potassium streams can lead in dos implies get it on konum deДџiЕџtirme. In the first step prospective repolarisation will be expidited attenuating the newest sum of your own step possibility to the fresh new course size which means probably broadening heart rate. Having said that a boost in potassium conductance into the slow diastolic depolarization will increase maximum diastolic potential and you can slow the interest rate from pacemaker depolarization leading to a more sluggish heartrate. The websites share depends on the latest properties of one’s potassium current. In case your newest predominates within asleep membrane prospective, such as for example with inwardly-rectifying potassium avenues, then your internet impression was with the diastolic depolarization. However if the energetic within significantly more depolarized potentials this might mainly dictate repolarisation. In principle one another outcomes may occur and the internet impact on heart rate would be tough to assume. Model during these points could be useful in helping the fresh facts of psychological outcomes regarding alterations in a specific potassium conductance. The fresh regulation of them currents could also be potentially crucial: increased potassium currents from inside the diastolic potential causing heart rate slowing. It is reasonably essential one action prospective stage adapts because of the reducing through the highest cardiovascular system cost or even regular pacemaking create falter. Adrenergic modulation out of repolarising potassium conductances was a process to ensure that and this is exactly discussed lower than.
There are strands out of proof directing so you’re able to activities where in fact the inhibitory heterotrimeric G-healthy protein are complexed towards channel and you will receptor just before activation [ 42 – 46 ]
All cardiac myocytes express a strong inwardly-rectifying potassium current. In ventricular cells this is known as IK1 and is accounted for by members of the Kir2.0 family of inward rectifiers [ 9 , 27 , 28 ]. In contrast in the SAN and atrial cells the current is less strongly inwardly-rectifying but is characteristically increased by muscarinic agonists such as acetylcholine and carbachol (“IKACh”) [ 29 ]. 0 subunits that in cardiac cells is constituted of Kir3.1 and Kir3.4 with perhaps some homomultimers of Kir3.4 [ 30 – 32 ]. The differential expression is not absolute for example there are some data indicating expression of IKACh in the ventricle [ 33 ].
Activation of IKACh is characteristically inhibited by muscarinic antagonists and activation is inhibited by pertussis toxin implicating heterotrimeric G-proteins in the regulation [ 34 ]. After some controversy, it became clear that it was the G?? subunit, not the inhibitory G?, that directly activated the channel complex and in many ways this is now the paradigmatic example of modulation of an effector by G?? [ 35 , 36 ].The domains on the Kir3.0 subunits that bind the G?? subunits and also the key residues on G?? have been mapped [ 36 , 37 ]. There are crystal structures of the channel complex with and without G?? subunits bound [ 38 ]. Anionic phospholipids particularly phosphatidylinositol- [ 4 , 5 ]-bisphosphate and sodium are known to be key modulators of the gating and a number of site-directed mutagenesis studies together with structural work have suggested models predicting how this might occur [ 38 – 40 ]. However the inhibitory G-protein ? subunit also participates in determining the selectivity of activation but not directly in activation itself [ 41 ].
So it most recent is actually a great heteromultimer out-of Kir3
The pathway delineated by genetic, physiological and pharmacological studies involved the activation of M2 muscarinic receptors and the dissociation of the inhibitory heterotrimer with the G?? activating GIRK channels in the SAN [ 47 – 50 ]. However the GTP bound inhibitory G? subunit can also inhibit adenylate cyclase and reduce levels of cAMP reducing If [ 51 ]. Thus there are two possible mechanisms for the reduction of heart rate via the parasympathetic arm of the autonomic nervous system: one involving GIRK and another via If. The relative importance of these has been debated over the years. Initially, low receptor occupancy was associated with If inhibition whilst higher receptor occupancy was needed for IKACh activation [ 52 ]. The cloning of the Kir3.0 channel subunits enabled the development of mice with global genetic deletion of GIRK4 (kcnj5). These mice together with other experimental observations clearly implicate GIRK channels and IKACh in heart rate regulation in physiological conditions [ 48 , 53 ].