This document discusses various neurotransmitters, neuromodulators, and receptors in the nervous system. It describes: 1) Two major classes of neurotransmitter receptors - ionotropic receptors which are ligand-gated ion channels, and G protein-coupled receptors which activate intracellular second messenger systems. 2) Examples of major inhibitory and excitatory neurotransmitters like GABA, glycine, glutamate, acetylcholine, and catecholamines and their receptor properties. 3) Other substances that modulate neurotransmission like neurotrophic factors, neuromodulators, and neuromediators.

1. RECEPTOR
PHARMACOLOGY
Biswajit Biswas

2. Neurotransmitter
A chemical released from a nerve ending that transmits
impulses from one neuron (nerve cell) to another neuron, or
to a muscle cell.
■ Functional Classification:
■ Excitatory Neurotransmitter- e.g.; Glutamate, Aspartate,
Adrenaline and Noradrenaline, Histamine, Nitric Oxide
and Acetylcholine.
■ Inhibitory Neurotransmitter– e.g.: GABA, Glycine,
Adrenaline and Noradrenaline, Dopamine and Serotonin.

3. Action Potential

4. Action Potential

5. Action Potential

6. Neurohormones
■ Peptide-secreting cells of the hypothalamic-hypophyseal
circuits (stress-regulating circuit from the brain into the body
linking the hypothalamus, the pituitary, and the adrenal glands)
originally were described as neurosecretory cells, receiving
synaptic information from other central neurons, yet secreting
transmitters in a hormone-like fashion into the circulation. The
transmitter released from such neurons was termed a
neurohormone, i.e., a substance secreted into the blood by a
neuron.
■ E.g.: oxytocin, arginine-vasopressin.

7. Neuromodulators
■ The distinctive feature of a modulator is that it originates
from nonsynaptic sites, yet influences the excitability of
nerve cells. Substances such as CO2 and ammonia,
arising from active neurons or glia, are potential
modulators through nonsynaptic actions. Similarly,
circulating steroid hormones, steroids produced in the
nervous system (i.e., neurosteroids), locally released
adenosine, other purines, eicosanoids, and NO are
regarded as modulators.

8. Neuromediators
■ Substances that participate in eliciting the
postsynaptic response to a transmitter fall under
this heading. The clearest examples of such
effects are provided by the involvement of cyclic
AMP, cyclic GMP, and inositol phosphates as
second messengers at specific sites of synaptic
transmission.

9. Neurotrophic Factors
■ Neurotrophic factors are substances produced within the CNS by neurons,
astrocytes, microglia or peripheral inflammatory or immune cells that assist
neurons in their attempts to repair damage. Seven categories of neurotrophic
peptides are recognized:
(1) the classic neurotrophins (NGF – Nurve Growth Factor, brain-derived neurotrophic
factor, and the related neurotrophins);
(2) the neuropoietic factors, which have effects both in brain and in myeloid cells (e.g.,
cholinergic differentiation factor [also called leukemia inhibitory factor], ciliary
neurotrophic factor, and some interleukins);
(3) growth factor peptides, such as EGF (Epidermal), TGF (Transforming) a and b, glial
cell–derived neurotrophic factor and activin A;
(4) the fibroblast growth factors;
(5) insulin-like growth factors;
(6) platelet-derived growth factors; and
(7) axon guidance molecules.

10. Receptor Properties
■ Biochemical techniques and molecular cloning studies have revealed two
major motifs and one minor motif of transmitter receptors.
■ The first, oligomeric ion channel receptors, are composed of multiple
subunits, usually with four transmembrane domains. The ion channel
receptors (ionotropic receptors or IRs) for neurotransmitters contain sites for
reversible phosphorylation by protein kinases and for voltage gating.
■ Receptors with this structure include nicotinic cholinergic receptors; the
receptors for the amino acids GABA, glycine, glutamate, and aspartate; and
the 5-HT3 receptor.
■ IRs can be ligand/transmitter gated, voltage gated (Na channel opens at -55
mili volts) or mechanical gated (opens by mechanical stretching).

11. Receptor Properties
■ The second major motif comprises the G protein–coupled
receptors (GPCRs), a large family of heptahelical receptors.
Activated receptors can interact with the heterotrimeric GTP-
binding protein complex.
■ Such protein–protein interactions can activate, inhibit, or
otherwise regulate effector systems such as adenylyl cyclase or
phospholipase C, and ion channels, such as voltage-gated Ca2+
channels or receptor-operated K+ channels.
■ GPCRs are employed by muscarinic cholinergic receptors, one
subtype each of GABA and glutamate receptors, and all other
aminergic and peptidergic receptors.

12. Receptor Properties
■ A third receptor motif is the growth factor receptor (GFR), a
membrane protein that has an extracellular binding domain that
regulates an intracellular catalytic activity, such as the atrial
natriuretic (Natriuresis is the process of sodium excretion in the
urine through the action of the kidneys - promoted by ventricular
and atrial natriuretic peptides) peptide–binding domain that
regulates the activity of the membrane bound guanylyl cyclase.
■ Dimerization of GPCRs and GFRs apparently contributes to their
activities, as does localization within or outside of caveolae (little
caves) in the membrane.

13. Receptor Properties
■ Postsynaptic receptivity of CNS neurons is regulated continuously
in terms of the number of receptor sites and the threshold required
to generate a response.
■ Receptor number often depends on the concentration of agonist
to which the target cell is exposed. Thus, chronic excess of agonist
can lead to a reduced number of receptors (desensitization or
down-regulation) and consequently to subsensitivity or tolerance
to the transmitter.
■ For many GPCRs, short-term down-regulation is achieved by the
actions of G protein–linked receptor kinases (GRKs) and
internalization of the receptors.

14. Receptor Properties
■ Conversely, deficit of agonist or prolonged pharmacologic
blockade of receptors can lead to increased numbers of receptors
and supersensitivity of the system.
■ These adaptive processes become especially important when
drugs are used to treat chronic illness of the CNS.
■ After prolonged exposure to drug, the actual mechanisms
underlying the therapeutic effect may differ strikingly from those
that operate when the agent is first introduced.

15. Receptor Properties
■ GPCR effector/transducer: Gi, Go, Gs, Gq, G11/12/13, PLC, PLA2, AC,
cGMP etc.
■ Excitatory Response:
■ Binds to Gs, Gq, G11/12/13  Stimulates or activates PLC, PLA2, AC 
Inhibit receptor operated K+ channel & activate voltage gated Ca2+
channel  Neuronal excitation.
■ Inhibitory Response:
■ Binds to Gi, Go  InhibitPLC, PLA2, AC  Stimulate receptor
operated K+ channel & inhibit voltage gated Ca2+ channel 
Neuronal inhibition.

16. GABA
■ GABA is the major inhibitory neurotransmitter in the mammalian CNS; it
mediates the inhibitory actions of local interneurons in the brain and may also
mediate presynaptic inhibition within the spinal cord.
■ GABA receptors have been divided into three main types: A, B, and C.
■ The most prominent subtype, the GABAA receptor, is a ligand-gated Cl– ion
channel, an “ionotropic receptor” that is opened after release of GABA from
presynaptic neurons.
■ The GABAB receptor is a GPCR.
■ The GABAC receptor is a transmitter-gated Cl– channel.
■ The GABAA receptor subunit proteins have been well characterized due to
their abundance.
■ The receptor also has been extensively characterized as the site of action of
many neuroactive drugs, notably benzodiazepines, barbiturates, ethanol,
anesthetic steroids, and volatile anesthetics.

17. GABA
■ The major form of the GABAA receptor contains at least three different subunits — α, β,
and γ.
■ All three subunits are required to interact with benzodiazepines.
■ The GABAB or metabotropic GABA receptor interacts with Gi to inhibit adenylyl cyclase,
activate K+ channels, and reduce Ca2+ conductance.
■ Presynaptic GABAB receptors function as autoreceptors, inhibiting GABA release, and
may play the same role on neurons releasing other transmitters.
■ There are two subtypes of GABAB receptors, 1a and 1b.
■ The GABAC receptor is less widely distributed than the A and B subtypes and is
pharmacologically distinct: GABA is more potent by an order of magnitude at GABAC
than at GABAA receptors, and a number of GABAA agonists (e.g., baclofen) and
modulators (e.g., benzodiazepines and barbiturates) seem not to interact with GABAC
receptors.
■ GABAC receptors are found in the retina, spinal cord, superior colliculus, and pituitary.

18. Glycine
■ Many of the features described for the GABAA receptor family apply to the inhibitory
glycine receptor that is prominent in the brainstem and spinal cord.
■ Multiple subunits assemble into a variety of glycine receptor subtypes, the complete
functional significance of which is not known.

19. Glutamate and Aspartate
■ Glutamate and aspartate have powerful excitatory effects on neurons in virtually every
region of the CNS. Glutamate and possibly aspartate are the principal fast (“classical”)
excitatory transmitters throughout the CNS.
■ Glutamate receptors are classed functionally either as ligand-gated ion channel
(“ionotropic”) receptors or as “metabotropic” GPCRs.
■ The ligand gated ion channels are further classified according to the identity of ligands that
selectively activate each receptor subtype and are broadly divided into N-methyl-D-
aspartate (NMDA) receptors and “non-NMDA” receptors.
■ The non-NMDA receptors include the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic
acid (AMPA), and kainate receptors.
■ Selective agonists and antagonists for NMDA receptors are available; the latter include
open-channel blockers such as phencyclidine (PCP or “angel dust”), antagonists such as 5,7-
dichlorokynurenic acid, which act at an allosteric glycine-binding site, and the novel
antagonist ifenprodil. In addition, the activity of NMDA receptors can be modulated by pH
and a variety of endogenous modulators including Zn2+, neurosteroids, arachidonic acid,
redox reagents & polyamines (spermine).

20. Glutamate and Aspartate
■ A well-characterized phenomenon involving NMDA receptors is the induction of long-term
potentiation (LTP). LTP refers to a prolonged (hours to days) increase in the size of a
postsynaptic response to a presynaptic stimulus of given strength.
Glutamate Excitotoxicity:
■ High concentrations of glutamate produce neuronal cell death. The cascade of events
leading to neuronal death is thought to be triggered by excessive activation of NMDA or
AMPA/kainite receptors, allowing significant influx of Ca2+ into the neurons.
■ Following a period of ischemia or hypoglycemia in the brain, NMDA receptor antagonists
can lessen neuronal cell death induced by activation of these receptors but cannot prevent
all such damage.
■ Glutamate-induced depletion of Na+ and K+ and small elevations of extracellular Zn2+ can
activate necrotic and pro-apoptotic cascades, leading to neuronal death.
■ Glutamate receptors are targets for therapeutic interventions (e.g., in chronic
neurodegenerative diseases and schizophrenia).

21. Catecholamines
■ The brain contains separate neuronal systems that utilize three different catecholamines—
dopamine (DA), norepinephrine (NE), and epinephrine (Epi).
■ Each system is anatomically distinct and serves separate, but similar, functional roles within
its field of innervation.
Dopamine
■ The CNS distributions of DA and NE differ markedly. More than half the CNS content of
catecholamine is DA, with large amounts in the basal ganglia (especially the caudate
nucleus), the nucleus accumbens (in hypothalamus), the olfactory tubercle, the central
nucleus of the amygdala, the median eminence and restricted fields of the frontal cortex.
■ Initial pharmacological studies distinguished two subtypes of DA receptors: D1 (which
couples to GS and activate adenylyl cyclase) and D2 (which couples to Gi to inhibit adenylyl
cyclase).
■ Subsequent cloning studies identified three additional genes encoding subtypes of DA
receptors: one resembling the D1 receptor, D5; and two resembling the D2 receptor, D3 and
D4, as well as two isoforms of the D2 receptor that differ in the length of their third
intracellular loops, D2 short and D2 long.

22. Dopamine
■ The D1 and D5 receptors activate adenylyl cyclase. The D2 receptors couple to multiple
effector systems, including the inhibition of adenylyl cyclase activity, suppression of Ca2+
currents, and activation of K+ currents.
■ The effector systems to which the D3 and D4 receptors couple are not well defined. DA
receptors have been implicated in the pathophysiology of schizophrenia and Parkinson’s
disease.
Norepinephrine
■ There are relatively large amounts of NE within the hypothalamus and in certain zones of
the limbic system (e.g., the central nucleus of the amygdala, the dentate gyrus of the
hippocampus). NE also is present in lower amounts in most brain regions.
■ Three types of adrenergic receptors (α1, α2, and β) and their subtypes occur in the CNS; all
are GPCRs and can be distinguished in terms of their pharmacological properties and their
distribution.
■ The β adrenergic receptors are coupled to Gs leading to stimulation of adenylyl cyclase
activity. The α1 adrenergic receptors are associated predominantly with neurons, while α2
adrenergic receptors are more characteristic of glial and vascular elements.

23. Norepinephrine
■ The α1 receptors couple to Gq to stimulate phospholipase C. The α1 receptors on neurons of
the neocortex and thalamus respond to NE with prazosin-sensitive, depolarizing responses
due to decreases in K+ conductance (both voltage sensitive and voltage insensitive).
■ α2 Adrenergic receptors are prominent on noradrenergic neurons, where they presumably
couple to Gi, inhibit adenylyl cyclase, and mediate a hyperpolarizing response due to
enhancement of an inwardly rectifying K+ channel.
Epinephrine-containing neurons are found in the medullary reticular formation and make
restricted connections to a few pontine and diencephalic nuclei. Their physiological
properties have not been identified.
Epinephrine

24. Acetylcholine – Nicotinic Receptor
■ The nicotinic ACh receptors (nAChRs) are members of a superfamily of ligand-gated ion
channels.
■ The receptors exist at the skeletal neuromuscular junction, autonomic ganglia, adrenal
medulla and in the CNS. They are the natural targets for ACh as well as pharmacologically
administered drugs, including nicotine.
■ The receptor forms a pentameric structure consisting of homomeric α and β subunits. In
humans, 8 α subunits (α2 through α7, α9 and α10) and three β subunits (β2 through β4) have
been cloned.
■ The nicotinic acetylcholine (ACh) receptor mediates neurotransmission postsynaptically at
the neuromuscular junction and peripheral autonomic ganglia.
■ ACh interacts with the nicotinic ACh receptor to initiate an end-plate potential (EPP) in
muscle or an excitatory postsynaptic potential (EPSP) in peripheral ganglia.
■ Classical fast excitatory transmission via cation channels.

25. Acetylcholine – Muscarinic Receptor
■ Actions of acetylcholine (ACh) are referred to as muscarinic based on the observation that
muscarine (an alkaloid derived from mushrooms) acts selectively at certain sites and,
qualitatively, produces the same effects as ACh.
■ Within the central nervous system (CNS), the hippocampus, cortex, and thalamus have high
densities of muscarinic receptors.
■ The cloning of complementary DNAs (cDNAs) encoding muscarinic receptors has identified
five distinct gene products, designated as M1 through M5.
■ All of the muscarinic receptor subtypes are G protein–coupled receptors (GPCRs).
■ Although selectivity is not absolute, stimulation of M1 and M3 receptors generally activates
the Gq-PLC-IP3 pathway and mobilizes intracellular Ca2+, resulting in a variety of Ca2+
mediated events, either directly or as a consequence of the phosphorylation of target
proteins.
■ In contrast, M2 and M4 muscarinic receptors couple to Gi to inhibit adenylyl cyclase and to Gi
and Go to regulate specific ion channels (e.g., enhancement of K+ conductance in cardiac
sinoatrial [SA] nodal cells).

26. Acetylcholine (Print 101,102,110,209-212)
■ Therapeutic Uses:
■ Acetylcholine (MIOCHOL-E) is available as an ophthalmic surgical aid for rapid production of
miosis.
■ Bethanechol chloride (URECHOLINE, others) is available in tablets and as an injection for use
as a stimulant of GI smooth muscle, especially the urinary bladder.
■ Pilocarpine hydrochloride (SALAGEN) is available as 5- or 7.5-mg oral doses for treatment of
xerostomia or as ophthalmic solutions (PILOCAR, others) of varying strength.
■ Methacholine chloride (PROVOCHOLINE) may be administered for diagnosis of bronchial
hyper-reactivity.

27. ■ Muscarinic receptor antagonists reduce the effects of ACh by competitively inhibiting its
binding to muscarinic cholinergic receptors. In general, muscarinic antagonists cause little
blockade at nicotinic cholinergic receptors; however, the quaternary ammonium derivatives
of atropine are generally more potent at muscarinic receptors and exhibit a greater degree
of nicotinic blocking activity, and consequently are more likely to interfere with ganglionic or
neuromuscular transmission.
■ At high or toxic doses, central effects of atropine and related drugs are observed, generally
CNS stimulation followed by depression; since quaternary compounds penetrate the blood–
brain barrier poorly, they have little or no effect on the CNS.
Acetylcholine – Muscarinic Receptor