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Intermingled cAMP, cGMP and calcium spatiotemporal dynamics in developing neuronal circuits.

Averaimo S, Nicol X - Front Cell Neurosci (2014)

Bottom Line: It is involved in a wide range of cellular processes that require independent regulation.However, our understanding of how this single second messenger achieves specific modulation of the signaling pathways involved remains incomplete.The subcellular compartmentalization and temporal regulation of cAMP signals have recently been identified as important coding strategies leading to specificity.

View Article: PubMed Central - PubMed

Affiliation: UMR_7210, Centre National de la Recherche Scientifique Paris, France ; UMR_S 968, Institut de la Vision, Sorbonne Universités, UPMC Univ Paris 06 Paris, France ; U968, Institut National de la Santé et de la Recherche Médicale Paris, France.

ABSTRACT
cAMP critically modulates the development of neuronal connectivity. It is involved in a wide range of cellular processes that require independent regulation. However, our understanding of how this single second messenger achieves specific modulation of the signaling pathways involved remains incomplete. The subcellular compartmentalization and temporal regulation of cAMP signals have recently been identified as important coding strategies leading to specificity. Dynamic interactions of this cyclic nucleotide with other second messenger including calcium and cGMP are critically involved in the regulation of spatiotemporal control of cAMP. Recent technical improvements of fluorescent sensors facilitate cAMP monitoring, whereas optogenetic tools permit spatial and temporal control of cAMP manipulations, all of which enabled the direct investigation of spatiotemporal characteristics of cAMP modulation in developing neurons. Focusing on neuronal polarization, neurotransmitter specification, axon guidance, and refinement of neuronal connectivity, we summarize herein the recent advances in understanding the features of cAMP signals and their dynamic interactions with calcium and cGMP involved in shaping the nervous system.

No MeSH data available.


Related in: MedlinePlus

Spatiotemporal dynamics of cAMP during axon outgrowth, axon guidance and topographic maps development. (A1) Axon elongation is enhanced in cultured retinal ganglion cell with an increased cAMP concentration. (A2) Electrical activity and calcium transients modulates cAMP synthesis by the soluble adenylyl cyclase (sAC/AC10). Both signals cooperate to regulate axon outgrowth. It is still unclear whether or not this signal transduction pathway is spatiotemporally restricted. (B1) Transient and local cAMP synthesis by light-mediated activation of an optogenetic AC (within the blue region) is sufficient to induce axon turning. (B2) Brief cAMP signal in filopodia induces an increase in the frequency of filopodia-restricted Ca2+ transients and a change of direction in axon outgrowth. cAMP/cGMP ratio sets the polarity of netrin-1-induced axon guidance. A high cAMP/cGMP ratio leads to attraction whereas a low ratio converts attraction into repulsion. (C1) cAMP signaling perturbation (lack of AC1, pharmacological blockade of ACs, or PKA blockade) prevents the axon repellents ephrin-As to induce axon retraction. (C2) Transient electrical activity- and calcium-dependent modulation of cAMP is required in growth cones for the backward movement of axons when exposed to ephrin-As.
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Figure 3: Spatiotemporal dynamics of cAMP during axon outgrowth, axon guidance and topographic maps development. (A1) Axon elongation is enhanced in cultured retinal ganglion cell with an increased cAMP concentration. (A2) Electrical activity and calcium transients modulates cAMP synthesis by the soluble adenylyl cyclase (sAC/AC10). Both signals cooperate to regulate axon outgrowth. It is still unclear whether or not this signal transduction pathway is spatiotemporally restricted. (B1) Transient and local cAMP synthesis by light-mediated activation of an optogenetic AC (within the blue region) is sufficient to induce axon turning. (B2) Brief cAMP signal in filopodia induces an increase in the frequency of filopodia-restricted Ca2+ transients and a change of direction in axon outgrowth. cAMP/cGMP ratio sets the polarity of netrin-1-induced axon guidance. A high cAMP/cGMP ratio leads to attraction whereas a low ratio converts attraction into repulsion. (C1) cAMP signaling perturbation (lack of AC1, pharmacological blockade of ACs, or PKA blockade) prevents the axon repellents ephrin-As to induce axon retraction. (C2) Transient electrical activity- and calcium-dependent modulation of cAMP is required in growth cones for the backward movement of axons when exposed to ephrin-As.

Mentions: Once neurons are polarized, axons grow over long distances to reach their synaptic partners. Axon elongation is dependent on cAMP signaling and high concentration of this second messenger favors axon outgrowth (Roisen et al., 1972; Cai et al., 2001; Shewan et al., 2002; Corredor et al., 2012). In this process as well, cAMP signaling is tightly linked to calcium to regulate axon outgrowth. Transient calcium elevations, termed calcium waves, have been visualized in the growth cone of extending axons. Calcium waves cover the entire growth cone at once and their kinetics is relatively slow. The frequency is inversely proportional to the speed of axon outgrowth in a wide range of models: lower frequency of calcium transients correlates with a high rate of axonal growth, while a high frequency is observed in slow growing axons (Gomez et al., 1995; Gomez and Spitzer, 1999; Tang et al., 2003). For instance in the developing spinal cord of X. laevis, Rohon-Beard neurons, ventral motor neurons and ascending interneurons exhibit a low frequency of calcium transients and a rapid outgrowth. In contrast, the frequency of calcium transients is higher in the slow growing dorso-lateral ascending interneurons (Gomez and Spitzer, 1999). A direct link between cAMP signals modulating axon outgrowth and calcium waves in growth cones has not been investigated so far. However, cAMP transients have been detected in axonal growth cones exposed to netrin-1, a guidance molecule that modulates both, the direction and the speed of axon elongation. cAMP transients require extracellular calcium influx and coincide with an increased frequency of calcium waves, that are not dependent on transmembrane AC activity (Nicol et al., 2011; Figure 3). The transient change in cAMP suggests that a temporal control might contribute to the coding strategy of cAMP signals regulating axon outgrowth.


Intermingled cAMP, cGMP and calcium spatiotemporal dynamics in developing neuronal circuits.

Averaimo S, Nicol X - Front Cell Neurosci (2014)

Spatiotemporal dynamics of cAMP during axon outgrowth, axon guidance and topographic maps development. (A1) Axon elongation is enhanced in cultured retinal ganglion cell with an increased cAMP concentration. (A2) Electrical activity and calcium transients modulates cAMP synthesis by the soluble adenylyl cyclase (sAC/AC10). Both signals cooperate to regulate axon outgrowth. It is still unclear whether or not this signal transduction pathway is spatiotemporally restricted. (B1) Transient and local cAMP synthesis by light-mediated activation of an optogenetic AC (within the blue region) is sufficient to induce axon turning. (B2) Brief cAMP signal in filopodia induces an increase in the frequency of filopodia-restricted Ca2+ transients and a change of direction in axon outgrowth. cAMP/cGMP ratio sets the polarity of netrin-1-induced axon guidance. A high cAMP/cGMP ratio leads to attraction whereas a low ratio converts attraction into repulsion. (C1) cAMP signaling perturbation (lack of AC1, pharmacological blockade of ACs, or PKA blockade) prevents the axon repellents ephrin-As to induce axon retraction. (C2) Transient electrical activity- and calcium-dependent modulation of cAMP is required in growth cones for the backward movement of axons when exposed to ephrin-As.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230202&req=5

Figure 3: Spatiotemporal dynamics of cAMP during axon outgrowth, axon guidance and topographic maps development. (A1) Axon elongation is enhanced in cultured retinal ganglion cell with an increased cAMP concentration. (A2) Electrical activity and calcium transients modulates cAMP synthesis by the soluble adenylyl cyclase (sAC/AC10). Both signals cooperate to regulate axon outgrowth. It is still unclear whether or not this signal transduction pathway is spatiotemporally restricted. (B1) Transient and local cAMP synthesis by light-mediated activation of an optogenetic AC (within the blue region) is sufficient to induce axon turning. (B2) Brief cAMP signal in filopodia induces an increase in the frequency of filopodia-restricted Ca2+ transients and a change of direction in axon outgrowth. cAMP/cGMP ratio sets the polarity of netrin-1-induced axon guidance. A high cAMP/cGMP ratio leads to attraction whereas a low ratio converts attraction into repulsion. (C1) cAMP signaling perturbation (lack of AC1, pharmacological blockade of ACs, or PKA blockade) prevents the axon repellents ephrin-As to induce axon retraction. (C2) Transient electrical activity- and calcium-dependent modulation of cAMP is required in growth cones for the backward movement of axons when exposed to ephrin-As.
Mentions: Once neurons are polarized, axons grow over long distances to reach their synaptic partners. Axon elongation is dependent on cAMP signaling and high concentration of this second messenger favors axon outgrowth (Roisen et al., 1972; Cai et al., 2001; Shewan et al., 2002; Corredor et al., 2012). In this process as well, cAMP signaling is tightly linked to calcium to regulate axon outgrowth. Transient calcium elevations, termed calcium waves, have been visualized in the growth cone of extending axons. Calcium waves cover the entire growth cone at once and their kinetics is relatively slow. The frequency is inversely proportional to the speed of axon outgrowth in a wide range of models: lower frequency of calcium transients correlates with a high rate of axonal growth, while a high frequency is observed in slow growing axons (Gomez et al., 1995; Gomez and Spitzer, 1999; Tang et al., 2003). For instance in the developing spinal cord of X. laevis, Rohon-Beard neurons, ventral motor neurons and ascending interneurons exhibit a low frequency of calcium transients and a rapid outgrowth. In contrast, the frequency of calcium transients is higher in the slow growing dorso-lateral ascending interneurons (Gomez and Spitzer, 1999). A direct link between cAMP signals modulating axon outgrowth and calcium waves in growth cones has not been investigated so far. However, cAMP transients have been detected in axonal growth cones exposed to netrin-1, a guidance molecule that modulates both, the direction and the speed of axon elongation. cAMP transients require extracellular calcium influx and coincide with an increased frequency of calcium waves, that are not dependent on transmembrane AC activity (Nicol et al., 2011; Figure 3). The transient change in cAMP suggests that a temporal control might contribute to the coding strategy of cAMP signals regulating axon outgrowth.

Bottom Line: It is involved in a wide range of cellular processes that require independent regulation.However, our understanding of how this single second messenger achieves specific modulation of the signaling pathways involved remains incomplete.The subcellular compartmentalization and temporal regulation of cAMP signals have recently been identified as important coding strategies leading to specificity.

View Article: PubMed Central - PubMed

Affiliation: UMR_7210, Centre National de la Recherche Scientifique Paris, France ; UMR_S 968, Institut de la Vision, Sorbonne Universités, UPMC Univ Paris 06 Paris, France ; U968, Institut National de la Santé et de la Recherche Médicale Paris, France.

ABSTRACT
cAMP critically modulates the development of neuronal connectivity. It is involved in a wide range of cellular processes that require independent regulation. However, our understanding of how this single second messenger achieves specific modulation of the signaling pathways involved remains incomplete. The subcellular compartmentalization and temporal regulation of cAMP signals have recently been identified as important coding strategies leading to specificity. Dynamic interactions of this cyclic nucleotide with other second messenger including calcium and cGMP are critically involved in the regulation of spatiotemporal control of cAMP. Recent technical improvements of fluorescent sensors facilitate cAMP monitoring, whereas optogenetic tools permit spatial and temporal control of cAMP manipulations, all of which enabled the direct investigation of spatiotemporal characteristics of cAMP modulation in developing neurons. Focusing on neuronal polarization, neurotransmitter specification, axon guidance, and refinement of neuronal connectivity, we summarize herein the recent advances in understanding the features of cAMP signals and their dynamic interactions with calcium and cGMP involved in shaping the nervous system.

No MeSH data available.


Related in: MedlinePlus