PubMed · 7413460
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A Dabrowski. 1980. [Accessory atrioventricular conduction].. https://pubmed.ncbi.nlm.nih.gov/7413460/
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Inactivating and noninactivating Na+ conductances are known to generate, respectively, the rising phase and the prolonged plateau phase of cerebellar Purkinje cell (PC) action potentials. These conductances have different voltage activation levels, suggesting the possibility that two distinct types of ion channels are involved. Single Purkinje cell reverse transcription-PCR from guinea pig cerebellar slices identified two Na+ channel alpha subunit transcripts, the orthologs of RBI (rat brain I) and Nach6/Scn8a. The latter we shall name CerIII. In situ hybridization histochemistry in rat brain demonstrated broad CerIII expression at high levels in many neuronal groups in the brain and spinal cord, with little if any expression in white matter, or nerve tracts. RBII (rat brain II), the most commonly studied recombinant Na+ channel alpha subunit is not expressed in PCs. As the absence of Scn8a has been correlated with motor endplate disease (med), in which transient sodium currents are spared, RBI appears to be responsible for the transient sodium current in PC. Conversely, jolting mice with a mutated Scn8a message demonstrates PC abnormalities in rapid, simple spike generation, linking CerIII to the persistent sodium current.
G protein-gated inward rectifier K+ channel subunits 1-4 (GIRK1-4) have been cloned from neuronal and atrial tissue and function as heterotetramers. To examine the inhibition of neuronal excitation by GIRKs, we overexpressed GIRKs in cultured hippocampal neurons from 18 day rat embryos, which normally lack or show low amounts of GIRK protein and currents. Adenoviral recombinants containing the cDNAs for GIRK1, GIRK2, GIRK4, and the serotonin 1A receptor were constructed. Typical GIRK currents could be activated by endogenous GABAB, 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 conductance by 1- to 2-fold, hyperpolarized the cell by 11-14 mV, and inhibited action potential firing by 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 stimulation of native GIRK currents in atrial myocytes. Two inhibitory effects of GIRK activation, hyperpolarization and diminution of depolarizing pulses, were simulated from the experimental data. These inhibitory effects are physiologically important in the voltage range between the resting membrane potential and the potential where voltage-gated Na+ and K+ currents are activated; that is where GIRK currents are outward.
Voltage-dependent sodium channels were studied in dissociated cerebellar Purkinje neurons from rats. In whole-cell recordings, a tetrodotoxin (TTX)-sensitive inward current was elicited when the membrane was repolarized to voltages between -60 and -20 mV after depolarizations to +30 mV long enough to produce maximal inactivation. At -40 mV, this "resurgent" current peaked in 8 msec and decayed with a time constant of 30 msec. With 50 mM sodium as a charge carrier, the resurgent current was on average approximately 120 pA. CA3 pyramidal neurons had no such current. The current may reflect recovery of inactivated channels through open states, because in Purkinje neurons (but not CA3 neurons) there was partial recovery from inactivation at -40 mV, coinciding with the rise of resurgent current. In single-channel recordings, individual channels gave openings corresponding to resurgent and conventional transient current. Action potentials were recorded from dissociated neurons under current clamp to investigate the role of the resurgent current in action potential formation. Purkinje neurons fired spontaneously at approximately 30 Hz. Hyperpolarization to -85 mV prevented spontaneous firing, and brief depolarization then induced all-or-none firing of conglomerate action potentials comprising three to four spikes. When conglomerate action potentials were used as command voltages in voltage-clamp experiments, TTX-sensitive sodium current was elicited between spikes. The falling phase of an action potential is similar to voltage patterns that activate resurgent sodium current, and thus, resurgent sodium current likely contributes to the formation of conglomerate action potentials in Purkinje neurons.