Nicotine induces calcium spikes in single nerve terminal varicosities: a role for intracellular calcium stores

Abstract

AbstractöWhile nicotine is known to act at neuronal nicotinic acetylcholine receptors (nAChRs) to facilitate neurotransmitter release, the mechanisms underlying this action are poorly understood. Some of its e¡ects are known to be mediated by presynaptic receptors. In the mouse vas deferens nicotine (10^30 WM) transiently increased the force of neurogenic contraction by 135 þ 25%, increased the amplitude of excitatory junction potentials by 74 þ 6% and increased the frequency of spontaneous excitatory junction potentials in four out of six preparations. Confocal microscopy and the calcium indicator Oregon Green 488 BAPTA-1 dextran were used to measure calcium concentration changes in the nerve terminals. Nicotine did not a¡ect the action potential-evoked calcium transient but instead triggered small, random £uctuations (`calcium spikes') in intra-varicosity calcium concentrations at an average frequency of 0.09 þ 0.02 Hz. These were insensitive to tetrodotoxin at a concentration that blocked action-potential evoked calcium transients (300 nM). They were abolished by the nAChR blocker hexamethonium (100 WM) and by both ryanodine (100 WM) and ca¡eine (3 mM), agents that modify calcium release from intracellular stores.We propose a novel mechanism whereby nicotine's action at nAChRs triggers calcium-induced calcium release from a ryanodine-sensitive calcium store in nerve terminals. This primes neurotransmitter release mechanisms and enhances both spontaneous and action potential-evoked neurotransmitter release. ß

Nicotinic receptor signaling in nonexcitable cells

“…In the substantia nigra nAChRmediated increases in [Ca] i inhibited by dantroline (Tsuneki et al, 2000). Local nAChR-mediated calcium changes at local nerve terminal varicosities in the vas deferens are almost completely due to CICR (Brain et al, 2001), suggesting a role for CICR in modulating local calcium-dependent events. Rapid nAChR-mediated calcium transients on somatic spines of ciliary ganglion neurons are not store-dependent, while a portion of global calcium signals are amplified by release from stores (Shoop et al, 2001).…”

Nonsynaptic Chemical Transmission Through Nicotinic Acetylcholine Receptors

“…Membrane nicotinic ion channels mediate fast Na ϩ and Ca 2ϩ influx, indeed, but the subsequent Ca 2ϩ accumulation below the receiver membrane takes longer. Slow Ca 2ϩ accumulation is corroborated by membrane voltage-sensitive Ca 2ϩ channels and by Ca 2ϩ release from intracellular stores (13,29,78,142,148,153,157,174,181). The Ca 2ϩ influx through the nAChR can add to the Ca 2ϩ response induced by synaptic activity or action potential back-propagation, which may lead to supralinear addition of inputs.…”

The Pharmacology of Nitric Oxide in the Peripheral Nervous System of Blood Vessels

“…In contrast, the response to nicotine is abolished by C 6 or other ganglionic blocking agents and also by amine transporter inhibitors (Su and Bevan, 1970;Toda, 1976) but is resistant to TTX. Studies on Ca 2ϩ concentration changes in single nerve terminal varicosities of the mouse vas deferens demonstrated that the nicotine action was insensitive to TTX at a concentration that blocked action potential-evoked Ca 2ϩ transients (Brain et al, 2001). These findings indicate that different mechanisms of action are involved in electrical and chemical stimulation responses.…”