The document discusses the structure and function of neurons. It notes that neurons are specialized cells that communicate via electrical and chemical signals. They contain dendrites that receive signals, a cell body, and an axon that transmits signals. At synapses, chemical neurotransmitters transmit signals between neurons or to other cell types. Neurons form circuits that allow for complex coordinated responses. The action potential involves changes in ion channel permeability that propagate electrical signals rapidly along axons. Calcium acts as an important intracellular messenger in neurons and other cell types, often working through the calcium sensor protein calmodulin.

1.  Nerve Cells:
 The nervous system regulates all aspects of body
function and is staggering in its complexity
 Millions of specialized neuron (nerve cells) sense
features of both the external and internal environments
and transmit this information to other nerve cells for
processing and storage
 Millions of other neurons regulate the contraction of
muscles and the secretion of hormones
 Therefore, neuron is the fundamental unit of all nervous
system
 Human brain - the control center that stores, computes
and transmits information - contains 1012 neurons
 Each forming as many as a 1000 connections with other
neurons
 The nervous system also contains neuroglial (glial)
cells that fill the spaces between neurons, nourishing
them and modulating their function

2.  Despite the complexity of the nervous system as a
whole, the structure and function of individual nerve
cells is understood in great detail
 Perhaps in more detail than for any other type of cell
 The function of a neuron is to communicate
information, which it does by two methods:
 Electric signals process and transmit
information within a cell
 Chemical signals transmit information between
cells, utilizing process similar to those
employed by other types of cells to signal each
other
 Information from the environment creates special
problems because of the diverse types of signals that
must be sensed - light, touch, pressure, sound,
odorants, the stretching of muscles

3.  Sensory neurons have specialized receptors that convert
these stimuli into electric signals
 These electric signals are than converted into chemical
signals that are passed on to other cells - called
interneurons - that convert the information back into
electric signals
 Ultimately, the information is transmitted to muscle-
stimulating motor neuron or to other neurons that
stimulate other types of cells such as glands
 Thus the out put of a nervous system is the result of its
circuit properties, that is, the wiring, or
interconnections, between neurons and the strength of
these interconnections
 At times, the properties of a nervous system must
change. For example:
 in the development of new memories

4.  Such changes can be explained as alterations in the
number and nature of the interconnections between
individual neuron
 Neurons, Synapses and Nerve Circuits;
 Since neuron is the fundamental unit of all nervous
systems, we will discuss the structural features that are
unique to these cells and
• the type of electrical signals that they use to
process and transmit information
 Then synapses - the specialized sites where neurons
send and receive information from other cells and
 Some of the circuits that allow groups of neurons to
coordinate complex processes

5.  Specialized Regions of Neurons Carry out Different
Functions;
• Most neuron contains four distinct regions with
differing functions:
- The cell body
- The dendrites
- The axon and
- The axon terminals
Fig 21.1 Lodish 3rd Ed
• The cell body contains the nucleus and lysosomes and
is the site where virtually all neuronal proteins and
membranes are synthesized
• Some proteins are synthesized in dendrites but axons
and axon terminals do not contain ribosome. Therefore
no protein synthesized there

6. Carries the nerve impulse
From receptor cell to
cell body
Carries the nerve impulse from
cell body to the spinal cord or
brain

7. • Proteins and membranes that are required for renewal
of the axon and nerve termini are synthesized in the cell
body and assembled there in to membranous vesicles or
multi-protein particles
• These are transported along microtubules down the
length of the axon
• This process is called orthograde axoplasmic
transport to the terminals
• Where they are inserted in to plasma membrane or
other organelles
• Axonal microtubules are also the tracks along which
damaged membrane and organelles move up the axon
toward the cell body
• Where they are degraded in lysosomes and this process
is called retrograde transport

8. • Most neurons have a single axon
• These are specialized for the conduction of a particular
type of electrical impulse away from the body, called
action potential
• Action potential is series of sudden changes in the
electric potential across the plasma membrane
Fig 21.2 Lodish 3rd Ed
• In resting or non-stimulated state the potential is ~ -60
mV (the inside is negative relative to the outside)
• This is similar to the potential in most non-neuronal
cells
• At the peak of an action potential the membrane
potential can be as much as +50 mV (inside positive), a
net change of ~ 110 mV
• This depolarization of the membrane is followed by a
rapid re-polirization or return to the resting potential

10. • These characteristics distinguish an action potential
from other types of changes in electrical potential
across the plasma membrane and allow an action
potential to move along an axon without diminution
• These and other changes in membrane potential are
generated and propagated by the opening and closing
of specific ion channel proteins in the neuron plasma
membrane
• Many of which have been cloned and characterized in
great detail
Fig 21.3 Lodish 3rd Ed
• Action potentials move rapidly, at speed up to 100
meters per second
• In humans, axon may be more than a meter long, yet it
takes only a few milliseconds for an action potential to
move along their length

12. • An action potential originates at the axon hillox, the
junction of axon and cell body and
• is actively conducted down the axon into the axon
terminals, small branches of the axon that form the
synapses or connections with other cells
• At synapses signals are passed:
 to other neurons
 to a muscle cell at a neuromuscular junction or
 to any of various other types of cells
• A single axon in the central nervous system can
synapse with many neurons and induce responses in all
of them simultaneously
• Most neurons have multiple dendrites, which extend
outward from the cell body and are specialized to
receive chemical signals from the axon termini of other
neurons

13. • Dendrites convert these signals into small electric
impulses and transmit them to cell body
• Neuronal cell bodies can also form synapses and thus
receive signals
Fig 21.4 Lodish 3rd Ed
• Particularly in the central nervous system, neurons have
extremely long dendrites with complex branches
• This allows them to form synapses with and receive
signals from a large number of other neurons, perhaps
up to a thousand
• Electric disturbance generated in the dendrites or cell
body spread to the axon hillox
• If the electrical disturbance there is great enough, an
action potential will originate and will be actively
conducted down the axon

15.  Synapses are Specialized Sites where Neurons Communicate
with Other Cells;
• Synapses are specialized sites where neurons
communicate with each other
• Synapses generally conduct signals in only one
direction
• An axon terminal from presynaptic cell sends signals
that are picked up by the postsynaptic cell
• There are two types of synapses which differ in both
structure and function:
i. Electrical
ii. Chemical
• Chemical synapses are much common than electric
synapses

16. Fig 21.5a, b Lodish 3rd Ed
• When action potential in the presynaptic cell reaches
an axon terminal, some of the vesicles fuse with the
plasma membrane, releasing their contents into the
synaptic cleft
• The neurotransmitter diffuses across the synaptic cleft
and after a lag period of about 0.5 millisecond binds
to receptors on the postsynaptic cells
• The bound neurotransmitter changes the ion
permeability of the postsynaptic plasma membrane
• Which in turn, changes the membrane’s electrical
potential at this point
• If postsynaptic cell is neuron, this electric disturbance
may be sufficient to induce an action potential
• If postsynaptic cell is a muscle, the change in
membrane potential following binding of the
neurotransmitter may induce contraction

17. Epinephrine or acetylcholine
Postsynaptic cell can be dendrite or cell body of another neuron, a muscle or gland cell or rarely even another axon. When
postsynaptic is muscle cell, the synapse is called neuromuscular junction or motor end plate
*
* Filled with NT (E, Ach)

18. • If a gland cell - neurotransmitter may induce hormone
secretion
• Now the question is how then signal terminates?
i. In some cases, enzymes attached to the fibrous
network connecting the cells destroy the
neurotransmitter after it has functioned
ii. In other cases, the signal is terminated when the
neurotransmitter diffuses away or is transported
back into the presynaptic cell
• In certain types of synapses, the postsynaptic neuron
sends signals to the presynaptic one
Fig 21.5c Lodish 3rd Ed
• Such retrograde signals can be gases such as
i. Nitric oxide (NO)
ii. Carbon monoxide or
iii. Peptide hormones

20. • This type of signaling modifies the ability of the
presynaptic cell to signal the postsynaptic one
• It is thought to be important in many types of learning
• Sometimes an axon terminal of one neuron will
synapse with the axon terminal of other neuron
Fig 21.6 Lodish 3rd Ed
• Such synapse may either inhibit or stimulate the ability
of an axon terminal to secrete the contents of its
synaptic vesicles and signal to a postsynaptic cell
• Neurons communicating by an electrical synapse are
connected by gap junctions
• Through which electric impulse can pass directly from
the presynaptic cell to the post synaptic one
Fig 21.7 Lodish 3rd Ed

21. We will discuss later how the molecular properties of such
synapses permit certain types of learning
/Stimulatory neuron

23. • Electric synapses allow a presynaptic cell to induce an
action potential in the postsynaptic cell with greater
certainty then chemical synapse and with out lag period
• Why….?
 Neurons are Organized into Circuits;
• In complex multi-cellular animals, such as insects and
mammals, signaling circuits consist of two or more
neurons and
• In some cases, highly specialized sensory receptor cells
which respond to specific environmental stimuli such
as:
- light
- heat
- stretching
- pressure and
- concentrations of many chemical substances

24. • In the type of circuit called a reflex arc:
• Interneurons connect multiple sensory and motor
neurons, allowing one sensory neuron to affect multiple
motor neurons and
• One motor neuron to be affected by multiple sensory
neurons
• In this way interneurons integrate and enhance reflexes
• For example, the knee-jerk reflex in humans involves a
complex reflex arc in which one muscle is stimulated to
contract while another is inhibited from contracting
Fig 21.8 Lodish 3rd Ed
• Such circuits allow an organism to respond to a sensory
input by the coordinated action of sets of muscles that
together achieve a single purpose

25. 1. Contraction
2. Inhibition of contraction
Net result of 1 and 2 is extension of leg at knee
joint

26. • The sensory and motor neurons of circuits such as the
knee-jerk reflex are contained with in the peripheral
nervous system
• These circuits send information to and receive
information from the central nervous system, which
comprises the brain and spinal cord and is composed
mainly of interneurons
Fig 21.9 Lodish 3rd Ed
• After having discussed the general features of neuron
structure, interactions and circuits, we will try to
understand mechanism by which a neuron generates
and conducts electric impulses
 The Action Potential and Conduction of Electric Impulses:
• We discussed earlier that an electric potential exists
across the plasma membrane of all cells
• The potential across the plasma membrane of cells can
be measured as follows:

28. Fig 21.11 Lodish 3rd Ed
• The potential across the surface membrane of most
animal cells generally does not vary with time
• In contrast, neurons and muscle cells- the principal
types of electrically active cells – undergo controlled
changes in their membrane potential
• They conduct action potentials along their membrane
by sequentially opening and closing ion channels that
are specific for Na+ and K+ ions
Fig 21.3 Lodish 3rd Ed
• Thus, we need to explain how the opening and closing
of ion channels and the resultant movement of small
numbers of ions from one side of the membrane to the
other causes changes in the membrane potential

31.  Cellular Effects of Ca2+ Depends on its Cytosolic
Level and often are Mediated by Calmodulin:
 Most intracellular Ca2+ ions sequestered in the
mitochondria and endoplasmic reticulum (ER) or other
cytoplasmic vesicles
 The concentration of free Ca2+ in the cytosol of any
cell is extremely low i.e. ≤10-7 whereas its
concentration in extra cellular fluid (~10-3 M) and in
ER is high
 Thus there is a large gradient tending to drive Ca2+
into cytosol across both the plasma membrane and ER
membrane
 When a signal transiently opens Ca2+ channels in either
of these membranes, Ca2+ rushes into cytosol,
dramatically increasing the local concentration and
triggering Ca2+ responsive proteins in the cell

32.  To use Ca2+ as an intracellular signal, cell must keep resting
cytosolic Ca2+ levels low
Fig 15.27 Alberts 3rd Ed
Fig 24.18 Zubay
 Two common pathways by which Ca2+ can enter the cytosol in
response to extra cellular signals
Fig 15.28 Alberts 3rd Ed
 Release of intracellular Ca2+ stores also is mediated by
ryanodine receptors in muscle cells and neurons
 In addition to IP3-sensitive Ca2+ channels, muscle cells
and neurons possess other Ca2+ channels called
ryanodine receptors (RYRs)
 This is because of their sensitivity to the plant alkaloids
ryanodine
Fig 20.44 Lodish 3rd Ed

37.  Two mechanisms operate to terminate the initial Ca2+
response:
 IP3 is rapidly dephosphorylated and thereby
inactivated by specific phosphatases
 Cytosolic Ca2+ is rapidly pumped out mainly
out of the cell
 Ca2+ Oscillations often Prolong the Initial IP3
Induced Ca2+ Response
 Ca2+ sensitive fluorescent indicators such as aequorin
or fura-2 are used to monitor cytosolic Ca2+ in
individual cells
 In which the IP signaling pathway has been activated
 The initial Ca2+ signal is often seen to propagate as a
wave through the cytosol from a localized region of the
cell
Fig 15.31 Alberts 3rd Ed

39.  Biological significance of Ca2+ oscillations is uncertain
 Their frequency often depends on the concentration of the
extra cellular signaling ligand and might, in principle, be
translated into a frequency dependent cellular response
 In hormone secreting pituitary cells, for example, stimulation
by an extra cellular signaling molecule induces repeated Ca2+
spikes
 Each of which is associated with a burst of hormone secretion
 It has been suggested that this arrangement might maximize
secretory out put while avoiding the toxic effects of a sustained
rise in cytosolic Ca2+

40.  Calmodulin is a Ubiquitous Intracellular Ca2+
Receptor
 A typical animal cell contains more than 107 molecules
of calmodulin, which can constitute as much as 1% of
the total protein mass of the cell
 Highly conserved protein, single polypeptide chain
containing 150 amino acids with four high affinity Ca2+
binding sites
 It undergoes a conformational change when it binds
Ca2+
Fig 15.34 Alberts 3rd Ed
 The allosteric activation of calmodulin by Ca2+ is
analogous to the allosteric activation of A kinase by
cAMP except that

42.  Ca2+/calmodulin has no enzyme activity itself but acts
by binding to other proteins
 Targets regulated by Ca2+/calmodulin are:
• various enzymes and
• membrane transport proteins
 For example in many cells Ca2+/calmodulin binds to
and activates the plasma membrane Ca2+-ATPase that
pumps Ca2+ out of the cell
 Ca2+/Calmodulin-dependent Protein Kinases
(CaM-Kinases) Mediate Most of the Actions of
Ca2+ in Animal Cells
 Most of the effects of Ca2+ in cells are mediated by
protein phosphorylation catalyzed by a family of
Ca2+/calmodulin-dependent protein kinases (CaM-
kinase

43.  These kinases phosphorylate serine or threonine in
proteins
 Like cAMP, the response of a target cell to an increase
in free Ca2+ concentration in the cytosol depends on
which CaM-kinase- regulated target proteins are
present in the cell
 The first CaM-kinase to be discovered was myosin
light chain kinase (MLCK) which activates smooth
muscle contraction and phosphorylase kinase which
activates glycogen breakdown
 The best studied example of such multifunctional
CaM-kinase is CaM- kinase II, which is found in all
animal cells but is specially enriched in the nervous
system
 When neurons that use catecholamine (dopamine,
nor-adrenaline or adrenaline) as their neurotransmitter
are activated, for example, the influx of Ca2+ through
voltage-gated Ca2+ channels in the plasma membrane
stimulates the cells to secrete their neurotransmitter

44.  The Ca2+ influx also activates CaM- kinase II to
phosphorylate and their by activate tyrosine hydrolase,
a rate limiting enzyme in catecholamine synthesis
 In this way both secretion and re-synthesis of the
neurotransmitter are stimulated when the cell is
activated
Fig 24.10, Zubay
 CaM-kinase has a remarkable property:
 it can function as a molecular memory device,
switching to an active state when exposed to
Ca2+/calmodulin and then
 remaining active even after the Ca2+ is
withdrawn
 This is because the kinase phosphorylate
itself i.e. autophophorylation as well as
other cell proteins when activated by Ca2+/
calmodulin

45. Tyrosine hydroxylase:
The amount and activity are regulated by cAMP-
dependent mechanism that are responsive to
neurotransmitter (acetylcholine)
CaM kinase II:

46. Fig 15.35 Alberts
 The cAMP and Ca2+ Pathways Interact:
 The cAMP and Ca2+ intracellular signaling pathways
interacts at several levels in the hierarchy of control
 First, cytosolic Ca2+ and cAMP levels can influence
each other. For example:
• Some forms of the enzymes that break down
and make cAMP are regulated by Ca2+/
calmodulin complexes - cAMP
phosphodiestrase and adenyl cyclase
• Similarly A-kinase can phosphorylate some
Ca2+ channels and pumps and alter their activity
for example:

48. • A-kinase phosphorylates the IP3 receptor in the
ER which can either inhibit or promote IP3-
induced Ca2+ release, depending on the cell
type
 Second, the enzymes directly regulated by Ca2+ and
cAMP can influence each other. For example:
• Some CaM-kinases are phosphorylated by A-
kinase
 Third, these enzymes can have interacting effects on
shared downstream target molecules. Thus
• A-kinase and CaM-kinases frequently
phosphorylate different sites on the same
proteins, which are thereby regulated by both
cAMP and Ca2+. For example:
- CREB (cAMP responsive element
binding protein) gene regulatory protein

49. Fig 20.41, Lodish 3rd Ed
Fig 15.36 Alberts 3rd Ed
Fig 15.16 Alberts 3rd Ed
Table 15.1 Lodish 6th Ed
 G Protein-Linked Cell-Surface Receptors that Regulate Ion
Channels
 Trimeric G proteins do not act exclusively by
regulating the activity of enzymes and altering the
concentration of cyclic nucleotides or Ca2+ in cytosol
 In some cases, they directly activate or inactivate ion
channels in the plasma membrane of the target cell

50. Epinephrine
SRnot only triggers
muscle contraction but
also *
*

54.  Mice Defective in the Hippocampal α-Ca2+- Calmodulin
Activated Protein Kinase are Impaired in Long-Term
Potentiation and in Spatial Learning – the Beginnings of a
Molecular Psychology:
 As observed, opening of the NMDA receptors is
associated with an increase in cytosolic Ca2+ and an
activation of several Ca2+-dependent enzymes
 Among these is the α-isoform of Ca2+-calmodulin-
dependent protein kinase II
 An enzyme found in abundance in neurons in the
hippocampus
 For this reason, workers suspected that this enzyme
was involved in induction of long-term potentiation and
 perhaps in certain types of learning
 To test this hypothesis, mice were genetically
engineered to have a deletion in the gene coding this
enzyme
 In most respect these mice grow and behave normally.
For example:

55.  Their abilities to eat and mate are normal and
 they have the coordinated motor skills to swim
normally in water
 However, cultured hippocampus neurons from these
mice are defective in the induction of long-term
potentiation
 More strikingly, the mice are impaired in a particular
type learning process, supporting the notion that
 α-isoform of Ca2+-calmodulin-dependent protein
kinase II is essential for induction of long-term
potentiation and that
 Long-term potentiation, in turn, is the electro-
physiological basis of a particular type of learning
 In a critical psychological test, mice are placed in a
round pool of opaque water
 To escape the water, the mice must swim to a
submerged platform

56.  The mutant mice can find the platform normally if it is
made visible by a flag, indicating that they can learn to
associate the flag with the submerged platform
 In contrast, when platform is hidden, the mice must
learn to find it from integrating multiple spatial
relationships between objects in the room surrounding
the pool (e.g., pictures on the wall) and the position of
the platform
 The mice defective with Ca2+-calmodulin-dependent
protein kinase take longer to learn to find the platform
than do their normal littermates
 This demonstrates that the α-isoform of Ca 2+-
calmodulin-dependent protein kinase II plays an
important role in spatial learning and
 That it is not essential for some types of non-spatial
learning
 As more hippocampus-specific proteins are identified
by molecular cloning techniques, scientists may
identify other enzymes or receptors essential for other
types of learning processes in mice

57.  Memory and Neurotransmitters:
 In its most general sense, learning is a process by which
human and other animals modify their behavior as a
result of experience or
 as a result of acquisition of information about the
environment
 Memory is a process by which this information is
stored and retrieved
 Psychologists have defined two types of memory
depending on how long it persists:
 Short term i.e. minutes to hours
 Long term i.e. days to years
 It is generally accepted that memory results from
changes in the structure or function of particular
synapses
 But until recently memory and learning could not be
studies with the tools of cell biology or genetics

58.  Most researchers believe that long term memory
involves the formation or elimination of specific
synapses in the brain and
 The synthesis of new mRNAs and proteins
 Because short term memory is too rapid to be attributed
to such gross alterations
 Some have suggested that changes in the release and
function of neurotransmitters at particular synapses are
the basis of short term memory
 Indeed, recent work has identified several types of
proteins that function to modify synaptic activity
 These proteins integrate two different signaling
pathways:
 they respond to two (or more) different but
coincident signals by generating an output that
is different from that produced by either signal
acting separately

59.  We shall see how two such proteins are involved in
elemental forms of learning?
 We begin with a molecular analysis of elemental forms
of learning in the fruit fly Drosophila and the sea slug
Aplysia and
 Then turn to long term potentiation, a form of learning
exhibited by many synapses in the mammalian brain
 Mutation in Drosophila Affect Learning and Memory:
 Remarkable as it sounds, fruit flies can be trained to
avoid certain noxious stimuli
 During the training period, a population of flies is
exposed to two different stimuli
 Either two odoriferous chemicals or two colors of light
 One of the two is associated with an electric shock
 The flies are then removed and placed in a new
apparatus and

60.  The two stimuli are repeated but with out the electric
shock
 The flies are tested for their avoidance of the stimulus
associated with the shock
 About half of the flies learn to avoid the stimulus
associated with shock and
 This memory persist for at lease 24 hr
 Pain staking observation of mutagenized flies has led
to the identification of six different genes in which
mutation cause defects in this learning process
 Two mutations that disrupt memory affect cAMP
levels are:
 One dunce, is due to a mutation in one of two
isoforms of the enzyme cAMP
phosphodiesterase