Inositol 1,4,5-Triphosphate-Evoked Responses in Midbrain Dopamine Neurons

Abstract

Synaptically released glutamate evokes slow IPSPs mediated by metabotropic glutamate receptors (mGluRs) in midbrain dopamine neurons. These mGluR IPSPs are caused by release of Ca(2+) from intracellular stores and subsequent activation of small-conductance Ca(2+)-activated K(+) channels (SK channels). To further investigate the intracellular mechanisms involved, the effect of photolyzing intracellular caged inositol 1,4,5-triphosphate (InsP(3)) on membrane conductance and intracellular Ca(2+) concentration ([Ca(2+)](i)) was examined in rat midbrain slices. Photolytic release of InsP(3) elicited a transient outward current and a sharp rise in [Ca(2+)](i) that lasted for approximately 5 sec. Apamin, a blocker of SK channels, abolished the InsP(3)-induced outward current without affecting the rise in [Ca(2+)](i). Depleting intracellular Ca(2+) stores with cyclopiazonic acid completely blocked both the outward current and the Ca(2+) transient elicited by InsP(3). InsP(3)-evoked Ca(2+) mobilization was not affected by blockade of ryanodine receptors with ruthenium red, whereas depleting ryanodine-sensitive Ca(2+) stores with ryanodine almost eliminated InsP(3)-induced Ca(2+) release. Increasing the size of intracellular Ca(2+) stores by means of prolonged depolarization added a late component to the outward current and a slow component to the rising phase of [Ca(2+)](i). These effects of depolarization were blocked by ruthenium red. These results show that InsP(3) activates SK channels by releasing Ca(2+) from InsP(3)-sensitive stores that also contain ryanodine receptors. Increasing intracellular Ca(2+) stores boosts InsP(3)-evoked responses by invoking Ca(2+)-induced Ca(2+) release through ryanodine receptors. This intracellular signaling pathway may play a significant role in regulating the excitability of midbrain dopamine neurons.

Prefrontal Cortex Stimulation Induces 2-Arachidonoyl-Glycerol-Mediated Suppression of Excitation in Dopamine Neurons

“…In addition, the lack of effect of MPEP indicates that mGluR5 is not involved, which is consistent with the expression of the mGluR1 subtype in DA cells (Testa et al, 1994;Kosinski et al, 1998). Interestingly, it has been reported that tetanic stimulation of excitatory fibers induces slow mGluR1-mediated excitatory and inhibitory responses (Shen and Johnson, 1997;Fiorillo and Williams, 1998) accompanied by rapid increases in intracellular Ca 2ϩ attributable to mobilization from the intracellular stores (Fiorillo and Williams, 1998;Guatteo et al, 1999;Morikawa et al, 2000). Thus, it might be speculated that rises in intracellular Ca 2ϩ leading to endocannabinoid synthesis and release might result from activation of intracellular pathways downstream of the activation of mGluR1.…”

Differential Regulation of Action Potential- and Metabotropic Glutamate Receptor-Induced Ca2+Signals by Inositol 1,4,5-Trisphosphate in Dopaminergic Neurons

“…The peak of the IP 3 -evoked outward current (I IP3 ) trace was not rounded even with a supramaximal intensity of UV pulse, suggesting that SK channels were not saturated by Ca 2ϩ . Our previous study also demonstrated approximately linear relationship between the I IP3 amplitude and [Ca 2ϩ ] i over a wide range in DA neurons (Morikawa et al, 2000). The amplitude of I IP3 elicited with a supramaximal UV intensity was 350 -700 pA (515 Ϯ 37 pA; n ϭ 10).…”

“…It should also be noted that DHPG-induced inhibition of I mGluR slowly recovered over a period of ϳ10 min after washout of DHPG, likely reflecting slow replenishment of Ca 2ϩ stores (Solovyova and Verkhratsky, 2003). It has been shown that IP 3 Rs and RyRs are expressed on a common pool of Ca 2ϩ stores in DA neurons (Morikawa et al, 2000). Recent evidence further suggests that the endoplasmic reticulum in DA neurons may actually be a single, interconnected lumen (Choi et al, 2006).…”

“…To directly demonstrate the role of IP 3 , we next performed flash photolysis of caged IP 3 , which releases Ca 2ϩ from intracellular stores and produces an SK-mediated outward current in DA neurons (Morikawa et al, 2000). IP 3 released by a single UV pulse at threshold intensity, which barely produced an outward current by itself (Ͻ20 pA), facilitated I AHP in a manner similar to perfusion of receptor agonists (n ϭ 5) (Fig.…”

Presynaptic BK type Ca2+-activated K+ channels are involved in prostanoid TP receptor-mediated inhibition of noradrenaline release from the rat gastric sympathetic nerves

“…In several types of neurons, however, elevation of intracellular Ca 2+ has been shown to activate Ca 2+ -activated K + channels, thereby producing a long-lasting after-hyperpolarization of an action potential to reduce neurotransmitter release from synaptic terminals (Cassell and McLachlan, 1987;Kawai and Watanabe, 1989;Marrion and Tavalin, 1998). The IP 3 -evoked activation of Ca 2+ -activated K + channels plays a role in regulating the excitability of rat midbrain dopamine neurons (Morikawa et al, 2000). Furthermore, ryanodine receptors have been shown to form a functional triad with Ca 2+ -activated K + channels and voltage-gated Ca 2+ channels located on the cell membrane, thereby directly shaping the spike repolarization of an action potential in bullfrog sympathetic neurons (Akita and Kuba, 2000).…”