Cellular Neuromodulation


Neuromodulation confers context‐sensitive flexibility to the signalling properties of neurons. The neuron is the central point of integration for an array of extracellular signals, and the output of the neuron, namely electrical activity and neurotransmitter release, is a function of the biochemical integration process. Remarkably, the choice between behaviours in different environmental or physiological contexts can often be ascribed to the biochemical processing that occurs at the level of a single neuron.

Keywords: firing pattern; bursting; action potential; ion channel; kinase; phosphatase; intracellular messenger; transmitter release; synaptic plasticity

Figure 1.

Current underlying the firing pattern of the prototypical bursting neuron. (a) Example of bursting activity. Modified from Levitan and Levitan (1988) Journal of Neuroscience8(4): 1152–1161. (b) The net membrane current (Imembrane) at any voltage is the sum of Ication, IK(Ca) and IK(IR). The arrow indicates a critical region of the current (I)–voltage (V) relationship that can be stabilized (membrane current near zero) or destabilized (membrane current farther away from zero) as a result of modulation.

Figure 2.

Biochemical mechanisms involved in neuromodulation. (a) Example of a typical intracellular messenger cascade. In this case, binding of the neurotransmitter or harmone (N) to its receptor (R) causes G protein‐dependent activation of adenylate cyclase (AC), which results in the formation of the messenger cyclic adenosine monophosphate (cAMP). cAMP activates protein kinase A, which in turn phosphorylates an ion channel (C). (b) Phosphorylation by protein kinases adds negatively charged phosphate groups, whereas dephosphorylation by protein phosphatases removes them. Adenosine triphosphate (ATP) is the phosphate donor for phosphorylation. (c) Example of a large signalling module containing several different types of proteins, formed by the association of proteins with specific interaction domains of an adaptor protein. A, cell adhesion molecule; ADP, adenosine diphosphate; CS, cytoskeletal protein; ICM, intracellular messenger; P, phosphate group.

Figure 3.

Modulation of neuronal firing patterns. (a) Top: Transition from the silent to spontaneously active state, as observed in extracellular recordings of Aplysia bag cell neurons. Bottom: Corresponding increase in cation channel activity in response to the same extracellular ligand used in (a), as observed in isolated membrane patches reinserted into neurons. (b) Top: Low concentrations of serotonin slow bursting in Aplysia neuron R15. Bottom: Increases in serotonin concentration switch R15 neurons from a bursting to a continuously active mode.

Figure 4.

(a,b) Serotonin modulation of action potential shape and transmitter release, and (c,d) synaptic remodelling with repeated serotonin stimulation, in Aplysia mechanosensory neurons. CRE, cyclic adenosine monophosphate (cAMP) response element protein; MAPK, mitogen‐activated protein kinase; PKA, protein kinase A.

Figure 5.

Dephosphorylated synapsin I tethers neurotransmitter‐filled vesicles to bundled actin filaments of the cytoskeleton. Phosphorylation of synapsin I by protein kinase A and calcium–calmodulin‐dependent protein kinase II (CaMKII) frees vesicles and causes bundled actin filaments to disaggregate. ADP, adenosine diphosphate; ATP, adenosine triphosphate; P, phosphate group.


Further Reading

Augustine G (1990) Regulation of transmitter release at the squid giant synapse by presynaptic delayed rectifier current. Journal of Physiology (London) 431: 343–364.

Greengard P, Valtorta F, Czernik AJ and Benfenati F (1993) Synaptic vesicle phosphoproteins and regulation of synaptic fuction. Science 259: 780–785.

Hawkins RD, Kandel ER and Siegelbaum SA (1993) Learning to modulate transmitter release: themes and variations in synaptic plasticity. Annual Review of Neuroscience 16: 625–665.

Hoffman DA and Johnston D (1998) Downregulation of transient K+ channels in dendrites of hippocampal CA1 pyramidal neurons by activation of PKA and PKC. Journal of Neuroscience 18: 3521–3528.

Kaczmarek LK and Levitan IB (eds) (1987) Neuromodulation: The Biochemical Control of Neuronal Excitability. New York: Oxford University Press.

Levitan IB (1994) Modulation of ion channels by phosphorylation and dephosphorylation. Annual Review of Physiology 56: 193–212.

Marrion NV (1997) Control of M‐current. Annual Review of Physiology 59: 483–504.

Wilson GF and Kaczmarek LK (1993) Mode‐switching of a voltage‐gated cation channel is mediated by a protein kinase A‐regulated tyrosine phosphatase. Nature 366: 433–438.

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Wilson, Gisela F(Apr 2001) Cellular Neuromodulation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0000264]