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Selective activation of heterologously expressed G protein-gated K⁺ channels by M₂ muscarinic receptors in rat sympathetic neurones

Jose M. Fernandez-Fernandez, Nicolas Wanaverbecq, Pam Halley, Malcolm P. Caulfield and David A. Brown *

G protein-regulated inward rectifier K⁺ (GIRK) channels were over-expressed in dissociated rat superior cervical sympathetic (SCG) neurones by co-transfecting green fluorescent protein (GFP)-, GIRK1- and GIRK2-expressing plasmids using the biolistic technique. Membrane currents were subsequently recorded with whole-cell patch electrodes.

Co-transfected cells had larger Ba²⁺-sensitive inwardly rectifying currents and 13 mV more negative resting potentials (in 3 mM [K⁺]_o) than non-transfected cells, or cells transfected with GIRK1 or GIRK2 alone.

Carbachol (CCh, 1-30 µM) increased the inwardly rectifying current in 70 % of GIRK1+ GIRK2-transfected cells by 261 ± 53 % (n = 6, CCh 30 µM) at -120 mV, but had no effect in non-transfected cells or in cells transfected with GIRK1 or GIRK2 alone. Pertussis toxin prevented the effect of carbachol but had no effect on basal currents.

The effect of CCh was antagonized by 6 nM tripitramine but not by 100 nM pirenzepine, consistent with activation of endogenous M₂ muscarinic acetylcholine receptors.

In contrast, inhibition of the voltage-activated Ca²⁺ current by CCh was antagonized by 100 nM pirenzepine but not by 6 nM tripitramine, indicating that it was mediated by M₄ muscarinic acetylcholine receptors.

We conclude that endogenous M₂ and M₄ muscarinic receptors selectively couple to GIRK currents and Ca²⁺ currents respectively, with negligible cross-talk.

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