Receptor

1. A molecule or molecular complex that binds other types of molecules in a specific, saturable manner.

2. A protein that responds to the binding of specific types of molecules by triggering a distinct type of change in cellular activity.

3. A specialized cell or organ at the front end of a sensory channel, capable of responding to specific types of sensory *stimuli by modulating its output to the nervous system.

'Receptor' is from recipio, 'to receive' in Latin. The families of receptors that concern us here are molecular (definition 1), specifically, proteins that respond to molecular stimuli by triggering cellular response (definition 2). Many types of these receptors reside on the surface membrane of the cell. Other types of molecular receptors are on the membrane of intracellular organelles or in the cytoplasm. We will focus on the cell-surface types. Receptor molecules also exist on and in sensory receptors cells (definition 3), where they respond to either chemical or physical stimuli, depending on the sensory modality that the organ or the cell transduces (Hudspeth 1989; Lagnado and Baylor 1992; GarciaAnoveros and Corey 1997; Herness and Gibertson 1999; Mombartes 1999). The receptive apparatus in sensory receptor cells is not prime candidate for fulfilling memory functions. This is because, being at the front end of the sensory channel, its alteration affects the input globally, whereas most learning is expected to involve a discriminative alteration in response to the input. We shall therefore concentrate on receptor proteins in the brain, particularly on those receptors that reside on "synaptic membranes and bind "neurotransmitters, neuromodulators, and growth factors. Such receptors subserve intercellular communication and could mediate or encode lasting modifications in circuit properties.

The term 'receptor' is used in pharmacology in a broader sense than in cellular neurobiology, and refers to any type of drug-target in living tissue (Ariens and Beld 1977; definition 1). The notion that drugs and poisons mimic or block physiological function by interacting with specific sites in the organism is at least over a century old. Langley (1905), studying the effects of the cholinergic ("acetylcholine) toxins nicotine and curare, was the first to term these sites 'receptive substances'. The decisive proof that receptors are specialized proteins was provided by studies of the nicotinic acetyl-choline receptor from the electric organ of electric fish. This receptor was isolated, reconstituted, and its gene was ultimately cloned (Numa et al. 1983; Changeux et al. 1984; for a personal view on the early history of the field, see Nachmansohn 1959). In its time, the cloning of the nicotinic receptor was a remarkable feat. Less then 20 years later, cloning receptor genes is a routine.

Before proceeding, a few semantic points should be clarified. Receptor proteins contain multiple functional components, which could reside in dissociatable subunits. One type of component is the 'binding site', which recognizes and binds specific molecules ('ligands', from 'bound' in Latin). Most receptors have multiple binding sites, commonly for different types of ligands. Another component is the 'effector', that part that performs the response function. This could be, for example, an "ion channel pore, or an active site of an enzyme (and see below). Some authors refer only to the binding site as a bona fide 'receptor' (Cooper et al. 1996). Receptors without an effector are sometimes called 'acceptors', and could, for example, play a part in regulating the level of specific ligands in the cell. Specific ligands could either activate the receptor, in which case they are termed 'agonists', or block it, in which case they are 'antagonists'. Ligands could also modulate the binding and action of other agonists. Finally, typically, a receptor protein is named after what is considered to be its major endogenous agonist, e.g. * glutamatergic, * dopaminergic. Similarly, the name of a receptor subtype refers to an endogenous ligand or to a drug or poison that displays selectivity for that subtype (e.g. a cholinergic muscarinic receptor). Sometimes, another structural or functional attribute is used for naming, e.g. a 'metabotropic' family of glutamate receptors (from 'metabolism'). In yet other cases, for the lack of a better alternative, arbitrary notations are employed, such as 1-n, a-v, etc. (e.g. Milligan et al. 1994). As the number of identified receptor types and variants keeps growing, notations tend to become cumbersome. The completion of the Human Genome project is expected to lead to a revision that will make the naming of receptor families more rational and convenient.

Cell-surface receptor proteins could be classified by their effector type. The three major effector types are ion channels, G proteins, and enzymes. Ion channel receptors are ligand-gated ion channels, for example, the nicotinic acetylcholine receptor is a Na+ channel, and the N-methyl-o-aspartate (NMDA) receptor primarily a *calcium channel.1 G-protein-coupled receptors belong to a superfamily of membrane proteins that contain seven hydrophobic transmembrane domains, and function by activating members of a family of regulatory protein called GTP-binding protein (abbreviated G protein; Gutkind 1998; intracellular signal transduction). The G protein, depending on its specific type, activates or inhibits the activity of other target proteins, such as enzymes, ion channels—or yet other receptors. Examples for G-protein-coupled receptors are muscarinic (*acetylcholine), dopaminergic, and metabotropic glutamatergic receptors. Finally, enzyme-linked receptors function as enzymes or are intimately associated with an enzyme. Examples are receptor *protein kinases (Numa et al. 1983; Marshall 1995). In situ, receptor proteins do not live in isolation; they interact dynamically with other membrane, cyto-skeletal and cytoplasmatic elements to form macro-molecular complexes, which together control specific facets of cellular state (Kim and Huganir 1999).

Generally speaking, synaptic receptors fit to fulfil the role of elementary hardware components in biological 'learning machines' (Dudai 1994a). They could serve as:

1. *Acquisition devices. Synaptic messages encoding stimulus information trigger a change in the target nerve cell by first activating receptor proteins. These receptors could therefore be regarded as 'cellular acquisition devices', implementing decoding and registration functions. Examples are various types of glutamatergic receptors that mediate excitatory transmission in the mammalian brain.

2. Transducers of *context. In the acquisition "phase the receptor could mediate information about the conditioned stimulus, about the "reinforcer (e.g. Shimizu et al. 2000), or about other, contextual "dimensions of the input.2 For example, receptors for acetylcholine in the mammalian brain transduce information on the novelty or saliency of stimuli (e.g. Naor and Dudai 1996). "Noradrenergic and dopaminergic receptors probably fulfil similar types of roles. An illustration of the role of receptors in encoding context at the cellular "level is provided by their ability to modulate stimulus-induced long-term alterations in synaptic efficacy (e.g. Kirkwood et al. 1999, also "long-term potentiation).

3. *Coincidence detectors. Receptor proteins could associate incoming stimuli. A popular example is the glutamatergic NMDA receptor, a molecular AND gate that integrates information encoded by glutamate and by membrane depolarization. Another example is provided by the role of serotonergic or peptidergic receptors3 in the conditioning of defensive reflexes in "Aplysia. In this case, the transmitter, which carries information about the unconditioned stimulus, activates a receptor-coupled enzyme, adenylyl cyclase. For optimal activation, however, the enzyme also requires calcium, which carries information about the conditioned stimulus. This dually activated receptor was reported to display the order and temporal-specificity constraints that are characteristic of "classical conditioning (Yovell and Abrams 1992).

4. Information storage devices. Use-dependent alterations in the sensitivity or availability of receptor molecules could encode long-lasting modifications in synaptic activity, and hence subserve the "persistence of the "engram over time (Changeux et al. 1984; Lynch and Baudry 1984). The idea is that even in the absence of other experience-dependent lasting synaptic modifications, increased availability or facilitated kinetics of a receptor is read-out by the retrieval input as a facilitated synaptic state. The proposed role of the AMPA-type glutamate receptor in long-term potentiation is a prominent example (Nayak et al. 1998; Shi et al. 1999).

In fulfilling the above roles, the specificity and effectiveness of the receptor-mediated information could be contributed by the sender (the ligand), the receiver (the receptor), or, most probably, by both. Candidate dimensions of specificity include the spatial (point of origin), temporal (rate and frequency), and intensity of the incoming stimulus, the location and concentration of the receptor on the cell surface, and the combinatorial activation of the receptor and its downstream intracellular signal transduction cascade(s) together with other types of receptors and cascades (e.g. Gutkind 1998; Madhani and Fink 1998).

The multiple roles of synaptic receptors in learning, memory, and retrieval marks them as promising targets for new memory-enhancing drugs ("dementia, "nootropics). For example, agonists of AMPA-type glutamate receptors have already been tested on humans and reported to improve memory (Ingvar et al. 1997).

Selected associations: Acquisition, Coincidence detector, Ion channel, Neurotransmitter, Stimulus

1Ligand-gated is contrasted with 'voltage-gated' channels (see *ion channel). Ligand-gated receptor channels are sometimes referred to also as 'chemically gated'. It makes sense to reserve the term 'ligand gated' to channels that are regulated by an extracellular ligand such as a neurotransmitter, and use the term 'chemically gated' to refer to channels that are regulated by either extracellular or intracellular compounds.

2The types of roles fulfilled by receptors in acquisition, including encoding of context, could also be fulfilled in 'retrieval.

3'Serotonergic' is a receptor for the neurotransmitter serotonin, and 'peptidergic' is a receptor for peptides that function as neurotransmitters, neuromodulators and hormones.

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