G Protein-Activated (GIRK) Current in Rat Ventricular Myocytes is Masked by Constitutive Inward Rectifier Current (I_K1)

Abstract

Inwardly-rectifying K⁺ channel subunits are not homogenously expressed in different cardiac tissues. In ventricular myocytes (VM) the background current-voltage relation is dominated by I_K1, carried by channels composed of Kir2.x subunits, which is less important in atrial myocytes (AM). On the other hand in AM a large G protein gated current carried by Kir3.1/3.4 complexes can be activated by stimulation of muscarinic M₂ receptors (I_K(ACh)), which is assumed to be marginal in VM. Recent evidence suggests that total current carried by cardiac inward-rectifiers (I_K(ATP), I_K(ACh), I_K1) in both, AM and VM is limited, due to K⁺ accumulation/depletion. This lead us to hypothesize that in conventional whole celI recordings I_K(ACh) in VM is underestimated as a consequence of constitutive I_K1. In that case a reduction in density of I_K1 should be paralleled by an increase in density of I_K(ACh). Three different experimental strategies have been used to test for this hypothesis: (i) Adenovirus-driven expression of a dominant-negative mutant of Kir2.1, one of the subunits supposed to form I_K1 channels, in VM caused a reduction in I_K1-density by about 80 %. In those cells I_K(ACh) was increased about 4 fold. (ii) A comparable increase in I_K(ACh) was observed upon reduction of I_K1 caused by adenovirus-mediated RNA interference.(iii) Ba²⁺ in a concentration of 2 µM blocks I_K1 in VM by about 60 % without affecting atrial I_K(ACh). The reduction in I_K1 by 2 µM Ba²⁺ is paralleled by a reversible increase in I_K(ACh) by about 100%. These data demonstrate that the increase in K⁺ conductance underlying ventricular I_K(ACh) is largely underestimated, suggesting that it might be of greater physiological relevance than previously thought.

Update on the cardiovascular profile of fingolimod in the therapy of relapsing-remitting multiple sclerosis (MS)

“…Clinically, these effects are transient because the receptor is rapidly desensitised and internalised. The effects seem limited to supraventricular structures, most probably due to a relatively weak expression of GIRK channels in ventricular myocytes (Beckmann et al, 2008).…”

The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels

“…Heart expresses GIRK1 and GIRK4 in sinoatrial node, atrium, and Purkinje fibers, and much less in the ventricle (Beckmann et al, 2008;Calloe, Goodrow, Olesen, Antzelevitch, & Cordeiro, 2013;Gaborit et al, 2007;Karschin et al, 1994;Yamada et al, 1998). Nevertheless, GIRK1's RNA is as abundant as the major G protein-independent inward rectifier, IRK1 (Kir2.1) in the ventricle (Marionneau et al, 2005).…”

“…Nevertheless, GIRK1's RNA is as abundant as the major G protein-independent inward rectifier, IRK1 (Kir2.1) in the ventricle (Marionneau et al, 2005). Accordingly, recent studies indicate a role for GIRK in shaping the action potential (AP) both in atrium and ventricle (Beckmann et al, 2008;Coote, 2013;Liang et al, 2014;Yang et al, 2010). The majority of cardiac GIRK channels are GIRK1/GIRK4 (GIRK1/4) heterotetramers (Bettahi, Marker, Roman, & Wickman, 2002;Nikolov & Ivanova-Nikolova, 2004a, 2004bYamada et al, 1998).…”

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

“…This current is a heteromultimer of Kir3.0 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 I KACh in the ventricle [33]. …”