Nh

FIGURE 12-3 Ionophore receptors for neurotransmitters are composed of subunits with four transmembrane domains and are assembled as tetramers or pentamers (at right). The predicted motif shown likely describes nicotinic cholinergic receptors for ACh, GABAa receptors for gamma-aminobutyric acid, and receptors for glycine.

TM4 Subunit

FIGURE 12-3 Ionophore receptors for neurotransmitters are composed of subunits with four transmembrane domains and are assembled as tetramers or pentamers (at right). The predicted motif shown likely describes nicotinic cholinergic receptors for ACh, GABAa receptors for gamma-aminobutyric acid, and receptors for glycine.

Voltage-dependent ion channels (Figure 12—2) provide for rapid changes in ion permeability along axons and within dendrites and for the excitation-secretion coupling that releases neurotransmitters from presynaptic sites. Ligand-gated ion channels, regulated by the binding of neurotransmitters, form a distinct group of ion channels (Figure 12-3). Within the CNS, variants of the K+ channels (the delayed rectifier, the Ca2+-activated K+ channel, and the after-hyperpolariz-ing K+ channel) regulated by intracellular second messengers repeatedly have been shown to underlie complex forms of synaptic modulation.

Cyclic nucleotide—modulated channels consist of two groups: the cyclic nucleotide—gated (CNG) channels, which play key roles in sensory transduction for olfactory and photoreceptors, and the hyperpolarization-activated, cyclic nucleotide—gated (HCN) channels. HCN channels are cation channels that open with hyperpolarization and close with depolarization; upon direct binding of cyclic AMP or cyclic GMP, the activation curves for the channels are shifted to more hyper-polarized potentials. These channels play essential roles in cardiac pacemaker cells and presumably in rhythmically discharging neurons.

TRP channels, named for their role in Drosophila phototransduction, are a family of hexas-panning receptors with a pore domain between the fifth and sixth transmembrane segments and a common 25-amino acid TRP "box" C-terminal of the sixth transmembrane domain; these channels are found across the phylogenetic scale from bacteria to mammals. Members of the TRPV subfamily serve as the receptors for endogenous cannabinoids, such as anandamide, and the hot pepper toxin, capsaicin.

Identification of Central Transmitters

The criteria for the identification of central transmitters require the same data used to establish the transmitters of the autonomic nervous system (see Chapter 6).

1. The transmitter must be shown to be present in the presynaptic terminals of the synapse and in the neurons from which those presynaptic terminals arise. Extensions of this criterion involve the demonstration that the presynaptic neuron synthesizes the transmitter substance, rather than simply storing it after accumulation from a nonneural source.

2. The transmitter must be released from the presynaptic nerve concomitantly with presynaptic nerve activity. This criterion is best satisfied by electrical stimulation of the nerve pathway in vivo and collection of the transmitter in an enriched extracellular fluid within the synaptic target area. The release of all known transmitter substances, including presumptive transmitter release from dendrites, is voltage-dependent and requires Ca2+ influx into the presynaptic terminal. However, transmitter release is relatively insensitive to extracellular Na+ or to tetrodotoxin, which blocks transmembrane movement of Na+.

3. When applied experimentally to the target cells, the effects of the putative transmitter must be identical to the effects of stimulating the presynaptic pathway. This criterion can be met loosely by qualitative comparisons (e.g., both the substance and the pathway inhibit or excite the target cell). More convincing is the demonstration that the ionic conductances activated by the pathway are the same as those activated by the candidate transmitter. The criterion can be satisfied less rigorously by demonstration of the pharmacological identity of receptors (order of potency of agonists and antagonists). Generally, pharmacological antagonism of the actions of the pathway and those of the candidate transmitter should be achieved by similar concentrations of antagonist. To be convincing, the antagonistic drug should not affect responses of the target neurons to other unrelated pathways or to chemically distinct transmitter candidates. Actions that are qualitatively identical to those that follow stimulation of the pathway also should be observed with synthetic agonists that mimic the actions of the transmitter.

Many brain and spinal cord synapses, especially those involving peptide neurotransmitters, apparently contain more than one transmitter substance. Substances that coexist in a given synapse are presumed to be released together, but in a frequency-dependent fashion, with higher frequency bursts mediating peptide release. Coexisting substances may either act jointly on the postsynaptic membrane, or affect release of transmitter from the presynaptic terminal. Clearly, if more than one substance transmits information, no single agonist or antagonist would faithfully mimic or fully antagonize activation of a given presynaptic element. Costorage and corelease of ATP and NE are an example.

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