Based on their structural and functional characteristics, the neurotransmitter receptor can be classified into two broad categories: metabotropic and ionotropic receptors. Ionotropic receptors form an ion channel pore. In contrast, metabotropic receptors are indirectly linked with ion channels on the plasma membrane of the cell through signal transduction mechanisms, often G proteins. Hence, G protein-coupled receptors are inherently metabotropic. Other examples of metabotropic receptors include tyrosine kinases and guanylyl cyclase receptors.
Both receptor types are activated by specific neurotransmitters. When an ionotropic receptor is activated, it opens a channel that allows ions such as Na+, K+, or Cl− to flow. In contrast, when a metabotropic receptor is activated, a series of intracellular events are triggered that can also result in ion channels opening but must involve a range of second messenger chemicals.
This class of receptors includes the metabotropic glutamate receptors, muscarinic acetylcholine receptors, GABAB receptors, and most serotonin receptors, as well as receptors for norepinephrine, epinephrine, histamine, dopamine, neuropeptides and endocannabinoids.
The G protein-coupled receptors have seven hydrophobic transmembrane domains. Most of them are monomeric proteins, although GABAB receptors require heterodimerization to function properly. The protein's N terminus is located on the extracellular side of the membrane and its C terminus is on the intracellular side.
The 7 transmembrane spanning domains, with an external amino terminus, are often claimed as being alpha helix shaped, and the polypeptide chain is said to be composed of ~ 450-550 amino acids.
Metabotropic receptors have neurotransmitters as ligands, which, when bound to the receptors, initiate cascades that can lead to channel-opening or other cellular effects. When a ligand (the neurotransmitter) binds to the receptor (the transducer) the latter activates a primary effector via the G-protein, which can go on to activate secondary messengers or have other effects. Since opening channels by metabotropic receptors involves activating a number of molecules in turn, channels associated with these receptors take longer to open than ionotropic receptors do, and they are thus not involved in mechanisms that require quick responses.:240 However, metabotropic receptors also remain open from seconds to minutes.:250–1 Thus they have a much longer-lasting effect than ionotropic receptors, which open quickly but only remain open for a few milliseconds. While ionotropic channels have an effect only in the immediate region of the receptor, the effects of metabotropic receptors can be more widespread through the cell.
Metabotropic receptors can either open or close channels in the cell membrane. They can make a membrane more excitable by closing K+ channels, retaining positive charge within the cell and thus reducing the amount of current necessary to cause an action potential.:242–3 Metabotropic receptors on the presynaptic membrane can inhibit or, more rarely, facilitate neurotransmitter release from the presynaptic neuron. These receptors can be further classified into receptor tyrosine kinases and G protein-coupled receptors, or GPCRs.:229
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