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Exotoxin‐insensitive G proteins mediate synaptically evoked muscarinic sodium current in rabbit sympathetic neurones.

1. The involvement of G proteins in the transduction pathway that links muscarinic receptors to the low‐threshold voltage‐dependent sodium current (INa,M) was studied in neurones from intact sympathetic prevertebral ganglia using the whole‐cell configuration of the patch‐clamp technique. Experiments were performed in the presence of the nicotinic receptor antagonists hexamethonium (50 microM) and d‐tubocurarine (50 microM). 2. INa,M was activated by either bath‐applying muscarinic agonists or stimulating the preganglionic splanchnic nerves. Synaptically and agonist‐mediated INa,M did not display significant run‐down or changes in their properties in cells tested, irrespective of whether the pipette solutions contained GTP. 3. Dialysis of sympathetic neurones with GDP beta S (500‐750 microM) decreased the amplitude of INa,M by approximately 65% compared with control neurones within 30 min. 4. In the absence of muscarinic receptor stimulation, intracellular dialysis with GTP gamma S (500 microM) for 10 min slowly and slightly (20‐25%) activated INa,M. GTP gamma S dialysis markedly slowed down the decay of INa,M after its transient activation with carbachol pulses (10‐20 s) or nerve stimulation (3‐5 s). The INa,M activation became fully irreversible 2.9 min after the start of GTP gamma S dialysis. Dialysing cells with the G protein activator AIF4‐led to a rapid but transient activation of INa,M. 5. Synaptically and agonist‐evoked INa,M were not affected in ganglia treated with 0.5‐1 microgram ml‐1 pertussis toxin (PTX) for 7‐24 h at 37 degrees C. Control experiments showed that this treatment severely reduced the PTX‐sensitive inhibition of N‐type calcium currents induced by carbachol (CCh) and noradrenaline. Application of NEM (N‐ethylmaleimide) for 2 min depressed the INa,M evoked in response to bath‐applied CCh by only 27%. 6. Incubating ganglia with 5‐10 micrograms ml‐1 of cholera toxin for 7 h had no effect on the carbachol‐induced INa,M but greatly potentiated (approximately 250%) the synaptically evoked INa,M, presumably via a presynaptic mechanism. 7. These results show that the coupling between muscarinic receptors and NaM channels is mediated by pertussis toxin‐ and cholera toxin‐insensitive G proteins, possibly of the Gq/11 or G12 class.