Activation of IMeuronal Nitric Oxide Synthase by M2 Muscarinic Receptors Associated with a Small Increase in Intracellular Calcium

Wang, Shou Zhen; Lee, Seok Yong; Sheng, Zhaoxue; Wotta, Diane R.; Parsons, Ann M.; El‐Fakahany, Esam E.

doi:10.1159/000139507

Cited by 15 publications

(6 citation statements)

References 16 publications

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“…It remains unclear how M 2 and M 4 receptors couple to increased levels of intracellular free Ca 2+ , since we were unable to detect increased phosphoinositide hydrolysis upon activation of either M 2 or M 4 receptors (data not shown). This confirms previous findings [20].…”

Section: Discussionsupporting

confidence: 94%

“…While chelating extracellular Ca 2+ expectedly eliminated the sustained cGMP response, it also greatly decreased the peak cGMP response. This suggests that extracellular Ca 2+ ifnlux plays a major role in eNOS activation, different from the mechanism of activation of nNOS by M 2 receptors [20]. It remains unclear how M 2 and M 4 receptors couple to increased levels of intracellular free Ca 2+ , since we were unable to detect increased phosphoinositide hydrolysis upon activation of either M 2 or M 4 receptors (data not shown).…”

Section: Discussionmentioning

confidence: 79%

“…We were able to show that both M 2 and M 4 receptors caused an increase in levels of intracellular free Ca 2+ in a concentration-dependent manner, although by considerably smaller magnitude than that observed from the M 1 receptor subtype [16,[19][20][21]. The response showed a transient peak followed by a lower plateau.…”

Section: Discussionmentioning

confidence: 81%

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M2 and M4 Muscarinic Receptor Subtypes Couple to Activation of Endothelial Nitric Oxide Synthase

Waid¹,

Chell²,

El‐Fakahany³

2000

Pharmacology

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In this report we studied coupling of M₂ and M₄ muscarinic acetylcholine receptors to activation of endothelial nitric oxide synthase (eNOS). Chinese hamster ovary cells that co-express the individual receptor subtypes and eNOS in a stable fashion were used as a model. Activation of eNOS was assayed by measuring increasing levels of cyclic GMP in admixed cells that contain guanylate cyclase. Activation of both M₂ or M₄ muscarinic receptors resulted in marked activation of eNOS, in a time- and concentration-dependent manner. The time course of the response exhibited a transient peak, followed by a sustained lower plateau. While the sustained phase was dependent on influx of extracellular calcium, the transient response showed dependency on both mobilization of intracellular calcium and extracellular influx.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 79%

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M2 and M4 Muscarinic Receptor Subtypes Couple to Activation of Endothelial Nitric Oxide Synthase

Waid¹,

Chell²,

El‐Fakahany³

2000

Pharmacology

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“…However, M2 receptors have been reported to activate low levels of PLC activity (Ashkenazi et al, 1987), and production of NO by M2 mAChRs has been reported in transfected Chinese hamster ovary (CHO) cells. Although no mechanism was definitively elucidated, the effects were thought to be the result of the release of intracellular calcium, not an influx of extracellular calcium (Wang et al, 1997). It is therefore very likely that the M2 muscarinic receptors expressed in the salamander retina could lead to modulation of other signaling pathways by NO.…”

Section: Ach and Nomentioning

confidence: 99%

Role of acetylcholine in nitric oxide production in the salamander retina

Cimini

Strang

Wotring

et al. 2008

J of Comparative Neurology

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Although acetylcholine is one of the most widely studied neurotransmitters in the retina, many questions remain about its downstream signaling mechanisms. In this study we initially characterized the cholinergic neurotransmitter system in the salamander retina by localizing a variety of cholinergic markers. We then examined the link between both muscarinic and nicotinic receptor activation and nitric oxide production by using immunocytochemistry for cyclic guanosine monophosphate (cGMP) as an indicator. We found a large increase in cGMP-like immunoreactivity (cGMP-LI) in the inner retina in response to muscarinic (but not nicotinic) receptor activation. Based on the amplification of mRNA transcripts, receptor immunocytochemistry, and the use of selective antagonists, we identified these receptors as M2 muscarinic receptors. Using double-labeling techniques, we established that these increases in cGMP-LI were seen in GABAergic but not cholinergic amacrine cells, and that the increases were blocked by inhibitors of nitric oxide production. The creation of nitric oxide in response to cholinergic receptor activation may provide a mechanism for modulating the well-known mutual interactions of acetylcholine-glycine-GABA in the inner retina. As GABA and glycine are the primary inhibitory neurotransmitters in the retina, signaling pathways that modulate their levels or release will have major implications for the processing of complex stimuli by the retina.

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“…Our laboratory has been involved in investigating the relationship between muscarinic receptor-mediated Ca2~signaling and nNOS activation (Surichamorn et al, 1990;Wang et al, 1996Wang et al, , 1997. It is interesting that the kinetics of nNOS activation by muscarinic Neuronal nitric oxide (NO) synthase (nNOS) rapidly metabolizes L-arginine into NO and L-citrulline on stimulation (Bredt, 1995).…”

mentioning

confidence: 99%

M₁ Muscarinic Receptors Stimulate Rapid and Prolonged Phases of Neuronal Nitric Oxide Synthase Activity: Involvement of Different Calcium Pools

Wotta

Parsons

et al. 1998

Journal of Neurochemistry

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This study shows that activation of M1 muscarinic receptors, when coexpressed in Chinese hamster ovary (CHO)‐K1 cells with neuronal nitric oxide (NO) synthase (nNOS), produces early and late phases of elevation of both intracellular Ca2+ concentration and nNOS activity. We examined the relationship between receptor‐mediated increases in intracellular Ca2+ concentration and activation of nNOS over both short and long intervals using guanosine 3′,5′‐cyclic monophosphate (cGMP) formation as a measure of nNOS activity. The rapid phase of nNOS activation was dependent on release of Ca2+ from intracellular stores in both the CHO M1/nNOS transfected cells and in neuroblastoma (N1E‐115) cells, in which muscarinic receptors and nNOS are endogenously expressed. Two single point mutations in the M1 muscarinic receptor that have previously been shown to uncouple differentially the receptor from phosphoinositide hydrolysis produced parallel attenuation of the rapid phase of nNOS activation. Characterization of the prolonged phase of nNOS activation was done using the conversion of l‐[3H]arginine to l‐[3H]citrulline as well as cGMP formation following stimulation of M1 muscarinic receptors for 60 min. Both responses were dependent on influx of extracellular Ca2+ and were accompanied by prolonged formation of NO at functionally effective levels as late as 60 min following receptor activation. Therefore, this study demonstrates for the first time the existence of two mechanistically distinct phases of nNOS activation that are dependent on different sources of Ca2+.

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Activation of IMeuronal Nitric Oxide Synthase by M2 Muscarinic Receptors Associated with a Small Increase in Intracellular Calcium

Cited by 15 publications

References 16 publications

M<sub>2</sub> and M<sub>4</sub> Muscarinic Receptor Subtypes Couple to Activation of Endothelial Nitric Oxide Synthase

M<sub>2</sub> and M<sub>4</sub> Muscarinic Receptor Subtypes Couple to Activation of Endothelial Nitric Oxide Synthase

Role of acetylcholine in nitric oxide production in the salamander retina

M₁ Muscarinic Receptors Stimulate Rapid and Prolonged Phases of Neuronal Nitric Oxide Synthase Activity: Involvement of Different Calcium Pools

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Activation of IMeuronal Nitric Oxide Synthase by M2 Muscarinic Receptors Associated with a Small Increase in Intracellular Calcium

Cited by 15 publications

References 16 publications

M<sub>2</sub> and M<sub>4</sub> Muscarinic Receptor Subtypes Couple to Activation of Endothelial Nitric Oxide Synthase

M<sub>2</sub> and M<sub>4</sub> Muscarinic Receptor Subtypes Couple to Activation of Endothelial Nitric Oxide Synthase

Role of acetylcholine in nitric oxide production in the salamander retina

M1 Muscarinic Receptors Stimulate Rapid and Prolonged Phases of Neuronal Nitric Oxide Synthase Activity: Involvement of Different Calcium Pools

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M₁ Muscarinic Receptors Stimulate Rapid and Prolonged Phases of Neuronal Nitric Oxide Synthase Activity: Involvement of Different Calcium Pools