ACTIVATION OF HETEROMERIC G-PROTEIN-GATED INWARD RECTIFIER K-TRANSFERINHIBITS THE EXCITABILITY OF HIPPOCAMPAL-NEURONS( CHANNELS OVEREXPRESSED BY ADENOVIRUS GENE)

G protein-gated inward rectifier K+ channel subunits 1-4(GIRK1-4) have been cloned from neuronal and atrial tissue and function as heterotet ramers, To examine the inhibition of neuronal excitation by GIRKs, we overexpressed GIRKs in cultured hippocampal neurons from 18 day rat em bryos, which normally lack or show low amounts of GIRK protein and cur rents. Adenoviral recombinants containing the cDNAs for GIRK1, GIRK2, GIRK4, and the serotonin 1A receptor were constructed, Typical GIRK cu rrents could be activated by endogenous GABA(B), serotonin 5-HT1A, and adenosine A1 receptors in neurons coinfected with GIRK1+2 or GIRK1+4. Under current clamp, GIRK activation increased the cell membrane cond uctance by 1- to 2-fold, hyperpolarized the cell by 11-14 mV,and inhib ited action potential firing bg increasing, the threshold current for firing by 2- to 3-fold, These effects were not found in non- and mock- infected neurons, and were similar to the effects of muscarinic stim u lation of native GIRK currents in atrial myocytes. Two inhibitory effe cts of GIRK activation, hyperpolarization and diminution of depolarizi ng pulses, were simulated from the experimental data. These inhibitory effects are physiologically important in the voltage range between th e resting membrane potential and the potential where voltage-gated Na and K+ currents are activated; that is where GIRK currents are outwar d.