Membrane current through atrial and neuronal G protein-gated inwardly rectifying K⁺ (GIRK) channels undergoes a fast (acute) desensitization upon rapid activation via appropriate receptors such as the muscarinic M₂ receptor in atrial myocytes using a saturating concentration of ACh (20 µM; Fig. 1). Pre-stimulation of GIRK current by a low concentration of ACh or via A₁ adenosine receptors resulted in a reduction of current induced by 20 µM ACh (I_K(ACh)). This reflected a decrease of the desensitizing component. It is assumed that acute desensitization does not represent classic receptor desensitization but reflects either a property of the G protein cycle (Chuang et al. 1998), or the channel itself (Bender et al. 2001). In the present study we investigated interactions between GIRK current and other inwardly rectifying K⁺ currents (I_K1, I_K(ATP)) in cultured adult rat atrial myocytes using whole cell voltage clamp.

WK rats were humanely killed in accordance with national legislation. The heart was removed and atrial myocytes were isolated by enzymatic perfusion. Cells were cultured and used experimentally for up to 1 week.

Activation of I_K(ATP) by either DNP or a channel opener (chromakalim) resulted in a reduction of I_K(ACh) and removal of its desensitizing component (Fig. 1). Overexpression of Kir2.1, one of the pore-forming subunits of I_K1 channels, by adenoviral gene transfer caused a large constitutive inward-rectifying current paralleled by a reduction in I_K(ACh) by ▓ge│ 90 %. Overexpressing Kir3.4 (GIRK4) by adenoviral gene transfer, resulted in an increased constitutive (receptor-independent) GIRK current and a concomitant reduction in I_K(ACh) and removal of its desensitizing component.

In summary, any increase in inwardly rectifying channel currents in atrial myocytes appears to result in a reduction of I_K(ACh) amplitude and removal of the desensitizing component. As the ACh-induced hyperpolarization has similar kinetic properties as I_K(ACh), we suggest that acute desensitization of the current is not an experimental artefact.

This work was supported by the Deutsche Forschungsgemeinschaft (Po212/9-3).