2013

http://informahealthcare.com/rstISSN: 1079-9893 (print), 1532-4281 (electronic)

J Recept Signal Transduct Res, 2013; 33(5): 267–275! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/10799893.2013.822890

REVIEW ARTICLE

Cell signaling, receptors, electrical effects and therapy in circadianrhythm

Peter Kovacic1 and Ratnasamy Somanathan1,2

1Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, USA and 2Centro de Graduados e Investigacion del Instituto

Tecnologico de Tijuana, Tijuana, B.C. Mexico

Abstract

Circadian rhythm has been the object of much attention. This review addresses the aspects ofcell signaling, receptors, therapy and electrical effects in a multifaceted fashion. The pinealgland, which produces the important hormones melatonin and serotonin, exerts a prominentinfluence, in addition to the supraschiasmatic nucleus. Many aspects involve free radicals whichhave played a widespread role in biochemistry.

Keywords

Cell signaling, circadian rhythm, electricaleffects, mechanism, receptors, therapy

History

Received 15 March 2013Revised 8 May 2013Accepted 6 June 2013Published online 5 August 2013

Introduction

Circadian rhythm originated billions of years ago in the early

stages of cellular life. It provided a means of facilitating

biological processes and combating adverse influences in

order to facilitate survival. The literature contains a host of

biological effects, both positive and negative, with which the

circadian clock is involved. This review illustrates the

multifaceted nature by concentrating on cell signaling,

receptors, electrical effects and therapy.

Cell signaling and signal transduction

The biological literature is replete with reports dealing with

cell signaling. This section contains examples involving the

circadian clock, with fundamental mechanistic aspects.

Data show that the circadian clock affects the daily rhythm

of adiponectin signaling components (1). High-fat diet,

followed by fasting, disrupts circadian expression of adipo-

nectin signaling pathways in muscle and adipose tissue. In a

2010 report, AKt and TOR signaling are shown to set the pace

of the circadian pacemaker (2). These two pathways, which

are major regulators of nutrient metabolism, cell growth and

senescense, impact the brain circadian clock that drives

behavioral rhythms in Drosophila. Elevated AKT or TOR

activity lengthens the circadian period, whereas reduced AKT

signaling shortens it. TOR signaling affects the timing of

nuclear accumulation of the circadian clock protein

TIMELESS. Activities of AKT and TOR pathways are

affected by nutrient/energy levels and endocrine signaling.

Findings provide an attractive link between the regulation of

the cellular redox state and the photic signaling pathways

implicated in circadian control (3).

Circadian clocks operate via transcriptional feedback

autoregulatory loops that involve the products of circadian

clock genes (4). How signaling influences chromatin remodel-

ing through histone modifications is therefore highly relevant

in the context of circadian oscillation. The most prominent

stimuli capable of synchronizing circadian oscillations to the

environment is light (5). This occurs through daily photic

signaling to the suprachiasmatic nucleus (SCN) hypothalamus,

which ultimately results in the appropriate phasing of the

various biological rhythms. Two critical aspects of circadian

biology are discussed, including photic signaling and the

communication between central and peripheral clocks.

One of the most fundamental and widespread mechanisms

of signal perception/transduction in prokaryotes is generally

referred to as the ‘‘two-component regulatory system (TCS)’’

(6). In the plant, TCS are crucially involved in the signal

transduction mechanism underlying the regulation of sophis-

ticated plant development in response to hormones (e.g.

cytokinin and ethylene). A unique TCS variant is essentially

integrated into the plant clock function that generates

circadian rhythms, and also tells us the time and season.

Recent progress with regard to studies on TCS is discussed.

Melatonin

Data demonstrate that melatonin (MEL) can directly modu-

late the circadian timing of SCN corresponding to dusk and

Address for correspondence: Peter Kovacic, Department of Chemistryand Biochemistry, San Diego State University, San Diego, CA 92182-1030, USA. E-mail: pkovacic@mail.sdsu.edu

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dawn; and MEL alters SCN cellular function via pertussis

toxin-sensitive G protein pathway that activates protein kinase

C (7). The function of CCK-A receptors was investigated for

visual signal transduction in regulation of the circadian clock

system (8). Novel ocular signal transduction controls mam-

malian circadian clock systems. A report deals with circadian

clocks, cell cycle, cancer and aging (9). Melatonin, the

primary hormonal product of the pineal gland is a

photoneuroendocrine transducer and biological pacemaker

that affects the seasonal adaption (photoperiodism) of higher

animals, governs a variety of reproductive and immunoregu-

latory functions and may play a key role in cancer, aging and

senescence. Not only does MEL production decline clinically

with age, but administration of MEL or the implantation of

pineal from young donors prolongs both median and absolute

survival times of older mice. There are a number of reports

that lifespan is altered in a variety of organisms reared in

constant light or darkness, or in non-24 hour light–dark

cycles. These environmental regimens are registered by the

pineal. The production and release of MEL exhibits circadian

rhythmicity in vivo, reflecting control by an endogenous

pacemaker and direct regulation by light, and, in the chick,

remains both rhythmic and photosensitive in vitro.

The effect of high-fat feeding on blood pressure regulation,

including hypothalamic redox signaling, as well as the changes

in diurnal pattern, circadian rhythms and response to restraint

stress, were investigated (10). The study shows that feeding

obesity-prone rats with high-fat diet results in elevated blood

pressure and delayed cardiovascular post-stress recovery, and

that these changes are paralleled by increase in the antioxidant

enzyme levels, possibly leading to superoxide-mediated

sympathoexcitation and hypertension.

Cell signaling mechanism

Earlier reviews discuss mechanistic aspects of cell signaling

involving redox chains and ROS (11–13), electrochemistry

(12), cancer (13), phosphates and sulfates (14). A novel cell

signaling mechanism was recently proposed (11). ROS have

begun to attract more interest. Molecules containing all of the

classical ET functionalities, acting as precursors of ROS,

would then be part of the scenario, in addition to other redox

moieties. In effect, cell signaling can be regarded as

proceeding via a long redox chain in which the standard

parameters of initiation, propagation and termination pertain,

involving conduit species with unshared electrons.

Receptors

Receptors play an important role in the biological domain.

Examples are provided herein in connection with circadian

rhythm. A prior review presented a unifying electrostatic

mechanism for receptor-ligand activity (15).

Synchronization

A hallmark of mammalian circadian timing system is

synchronization of physiology and behavior, but when this

synchronization is disturbed, chronic diseases, such as

metabolic syndrome and depression, may develop (16).

Studies show that nuclear receptors of the Rev-Erb family

impact the circadian oscillator and its metabolic output and

this can be modified with specific agonists. Hence, resyn-

chronization of metabolic pathways by manipulation of the

circadian oscillator using REV-ERB-specific agonists may

represent a feasible therapeutic concept to target diseases

rooted in a misaligned circadian system.

Pineal gland/melatonin and serotonin

The role of the pineal gland is to translate the rhythmic cycles

of night and day encoded by the retina into hormonal signals

that are transmitted to the rest of the neuronal system in the

form of serotonin and melatonin synthesis and release (17).

Production of both melatonin and dopamine is regulated by

D-4 receptors. Through alpha (1B)-D-4 and beta (1)-D-4

receptor heteromers, dopamine inhibits adrenergic receptor

signaling and blocks the synthesis of melatonin induced by

adrenergic receptor ligands. The data provide a new perspec-

tive on dopamine function and constitute the first example of

circadian-controlled receptor heteromer. The unanticipated

heteromerization between adrenergic and dopamine D-4

receptors provides a feedback mechanism for the neuronal

hormone system in the form of dopamine to control circadian

inputs.

Circadian rhythms refer to biological processes that

oscillate with a period similar to 24 h (18). These rhythms

are sustained by a molecular clock and provide a temporal

matrix that ensures the coordination of homeostatic processes

with the periodicity of environmental challenges. The circa-

dian molecular clock controls the expression and function of

Toll-like receptor 9 (TLR9). The findings unveil a direct

molecular link between the circadian and innate immune

systems with important implications for immunoprophylaxis

and immunotherapy.

Serotonin receptor 7 is widespread in the forebrain (19).

Studies have shown that this receptor is involved in learning/

memory, regulation of mood and circadian rhythms. The

modulatory effect of a novel agonist LP-211 was assessed in

mice. LP-211 is able to act consistently onto exploratory

motivation, anxiety-related profiles and spontaneous circa-

dian rhythm. Agonist modulation of 5-HT (7) receptors might

turn out to be beneficial for sleep and/or anxiety disorders.

The nuclear receptor REV-ERB alpha mediates circadian

regulation of innate immunity through selective regulation of

inflammatory cytokines (20). Diurnal variations in inflam-

matory and immune function are evident in the physiology

and pathology of humans and animals. The magnitude of

response exhibited pronounced temporal dependence, yet only

within a subset of proinflammatory cytokines. Disruption of

the circadian clockwork in macrophages occurred by condi-

tional targeting of key clock gene gating of endotoxin-induced

cytokine response in cultured cells and in vivo. Loss of

circadian gating was coincident with suppressed rev-erb alpha

expression, implicating this nuclear receptor as a potential

link between the clock and inflammatory pathways. This

finding was confirmed in vivo and in vitro through genetic

and pharmacological modulation of REV-ERB alpha activity.

Circadian gating endotoxin response was lost despite main-

tenance of circadian rhythmicity within these cells. Human

macrophages show circadian clock gene oscillations and

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rhythmic endotoxin responses. Administration of a synthetic

REV-ERB ligand is effective at modulating the production

and release of the proinflammatory cytokine OL-6. The

macrophage clockwork provides temporal gating of systemic

responses to endotoxin, and identifies REV-ERB alpha as the

key between the clock and immune function. REV-ERB alpha

may therefore represent a unique therapeutic target in human

inflammatory disease.

The endogenous melatonin signal facilitates re-entrain-

ment of the circadian system to phase advances on the level of

the suprachiasmatic nuclei molecular clockwork by acting

upon MT2 receptors (21). The expression of genes involved in

xenobiotic detoxification is under the control of the circadian

clock (22). The aryl hydrocarbon receptor (AhR) is one of the

transcription factors responsible for the induction of detoxi-

fication enzymes in response to xenobiotic toxins, and the

expression of AhR has been suggested to be regulated by a

circadian oscillator. CLOCK protein affects the toxin-induced

expression of detoxification enzymes through modulating the

activity of AhR. The findings provide a molecular link

between the circadian clock and xenobiotic detoxification. An

investigation deals with circadian behavior of leptin and its

receptor expression in human adipose tissue (AT) (23). Leptin

expression showed an oscillatory pattern that was consistent

with circadian rhythm in cultured AT. Similar patterns were

noted for the leptin receptor. Circadian rhythmicity was

demonstrated in leptin and its receptor in human AT cultures

in a site-specific manner. This knowledge paves the way for a

better understanding of the autocrine/paracrine role of leptin

in human AT.

Sleep and feeding rhythms are highly coordinated across

the circadian cycle, but the brain sites responsible for this

coordination are not known (24). The role of neuropeptide

Y(NPY) receptor-expressing neurons in the mediobasal

hypothalamus (MBH) was studied. Results suggest that

MBH is required for the essential task of integrating sleep–

wake and feeding rhythms, a function that allows animals

to accommodate changeable patterns of food availability.

NPY receptor-expressing neurons are key components of the

integrative function.

Light-induced phase shifts of hamster circadian activity

rhythms are modulated by GABA(B) receptors (25). Recently

positive allosteric modulators (PAM)s at GABA(B) receptors

were described. The data are consistent with the possibility

that PAMs at GABA(B) receptors inhibit light-induced phase

advances, yet they also possess ‘‘allosteric agonist’’ actions

at the population of GABA(B) receptors modulating light-

induced phase delays. GABA(B) receptors warrant further

investigation as agents for modulation of circadian dysfunc-

tion associated with CNS disorders, such as depression.

Melatonin modulates many important functions within the

eye by interacting with a family of G-protein-coupled

receptors that are negatively coupled with adenylate cyclase

(26). In the mouse, melatonin receptors type 1 (MT(1))

mRNSs have been localized to photoreceptors, inner retinal

neurons and ganglion cells, thus suggesting that MT(1)

receptors may play an important role in retinal physiology.

Indeed, absence of the MT(1) receptors has a dramatic effect

on the regulation of the daily rhythm in visual processing, and

on retinal cell viability during aging. MT(1) signaling plays

an important role in the circadian regulation of the mouse

electroretinogram (ETG), and in particular, on rod and cone

photoreceptors and on intrinsically photosensitive ganglion

cells. MT(1) signaling is necessary for the circadian rhythm in

the photopic ERG. In the mammalian retina, dopamine

binding to the dopamine D-4 receptor (D4R) affects a light-

sensitive pool of cyclic AMP by negatively coupling to the

type 1 adenylyl cyclase (AC1) (27). Data demonstrate that

stimulating the D4R is essential in maintaining the normal

rhythmic production of AC1 from transcript to enzyme

activity. Thus, dopamine/D4R signaling entrains the rhythm

of Adcy 1 expression and, consequently, modulates the

rhythmic synthesis of cyclic AMP in mouse retina.

In mammals, the master clock in the SCN of the

hypothalamus is composed of numerous synchronized

oscillating cells that drive daily behavioral and physiological

processes. Several entrainment pathways can reset the circa-

dian system regularly and also modulate neuronal activity

within SCN (28). Results suggest that glycine is able to

modulate circadian activity by acting directly on its specific

receptors in SCN neurons. Glutamate released from retinal

ganglion cells conveys information about the daily light:dark

cycle to master circadian pacemaker neurons within the

suprachiasmatic nucleus that then synchronize internal circa-

dian rhythms with the external day-length (29). Glutamate

activation of ionotropic glutamate receptors in the suprachi-

asmatic nucleus is well established. Dysfunctions in human

circadian rhythms have been implicated in some forms of

depression, and metabotropic glutamate receptor ligands are

shown to be capable of modifying light-induced phase shifts

of circadian activity rhythms.

The molecular basis of circadian rhythm control by

melatonin receptors (MTs) was investigated by means of the

mitochondrial ribonucleic acid (mRNA) expression of three

types of MTs in different tissues of the olive flounder (30).

Findings reinforce the hypothesis that MTs are active in

processing light information and that these genes are

regulated by the circadian clock and light, thus suggesting

that MTs play an important role in daily and circadian

variations in the brain and retina of olive flounders. 5-HT7

receptors in the dorsal raphe nucleus (DRN) influence

circadian rhythms, sleep and serotonin release (31).

Interactions between 5-HT7 receptors and glutamatergic and

GABAerhic neurons have been demonstrated previously.

Studies tested the hypothesis that GABAergic and/or

glutamatergic neurons mediate phase shifts induced by

activation of DRN 5-HT7 receptors. Findings suggest that

the mechanism mediating DRN 5-HT7 receptor induction of

phase advances involves decreased glutamatergic neurotrans-

mission, and furthermore, that inhibition of DRN GABAergic

neurotransmission causes a phase advance.

Other receptors

Systemic low doses of the endotoxin lipopolysaccharide

(LPS) induce phase delays of locomotor activity rhythms in

mice (32). Results show that LPS-induced circadian responses

are mediated by the Toll-like receptor 4. Many behavioral

and physiological processes, including locomotor activity,

blood pressure, body temperature, fasting-feeding cycles,

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sleep–wake cycles, display metabolic diurnal rhythms (33).

The biological clock ensures proper metabolic alignment of

energy substrate availability and processing. Studies in

animals and humans highlight a strong link between circadian

disorders and altered metabolic responses and cardiovascular

events. Shift work, for instance, increases the risk to develop

metabolic abnormalities resembling the metabolic syndrome.

Nuclear receptors have long been known as metabolic

regulators. Several of them (i.e. Rev-erb alpha, ROR alpha

and peroxisome proliferation activated receptors) are sub-

jected to circadian variations and are integral components

of molecular clock machinery. These nuclear receptors

regulate downstream target genes in a circadian manner,

acting to properly gate metabolic events to the appropriate

circadian time.

Chronic stimulation of the hypothalamic vasoactive intes-

tinal peptide receptor lengthens circadian period in mice and

hamster. Evidence suggests that circadian rhythms are

regulated through diffusible signals generated by the SCN

(34). Vasoactive intestinal peptide (VIP) is located in SCN

neurons positioned to receive photic input from the

retinohypothalamic tract and transmit information to other

SCN cells and adjacent hypothalamic areas. Studies using

knockout mice indicate that VIP is essential for synchrony

among SCN cells and for the expression of normal circadian

rhythms. The results suggest that VIP signaling in the SCN

may play two roles, synchronizing SCN neurons and setting

the period of the SCN as a whole.

The recurring light/dark cycle that has a period length of

about 24 hours has been internalized in various organisms in

the form of a circadian clock (35). This clock allows a precise

orchestration of biochemical and physiological processes in

the body, thus improving performance. The clock component

PERIOD2 (PER2) can coordinate transcriptional regulation of

metabolic, physiological or behavioral pathways by interact-

ing with nuclear receptors. PER2 appears to act as a co-

regulator of nuclear receptors linking clock function and

transcriptional regulation at the level of protein–protein

interactions. A report provides additional evidence for

modulation of nuclear receptor-dependent transcription by

PER2 underscoring the broad implications. The findings

provide a base for the understanding of various disorders,

including mood, that have their roots in a temporal deregu-

lation of basic metabolic processes.

The glutamatergic neurotransmission in the SCN plays a

central role in the entrainment of the circadian rhythms to

environmental light–dark cycles (36). Although the glutama-

tergic effect operating via N-methyl-D-aspartate receptor

(NMDAR) is well elucidated, much less is known about the

role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propio-

nic acid receptor (AMPAR) in circadian entrainment. The

data demonstrate that activation of AMPAR is capable of

phase-shifting the circadian clock both in vivo and in vitro,

and are consistent with the hypothesis that activation of these

receptors is a critical step in the transmission of photic

information to the SCN.

Daily rhythms of behavior are controlled by a circuit of

circadian pacemaking neurons (37). In Drosophila, 150

pacemakers participate in this network, and recent observa-

tions suggest that the network is divisible into M and

E oscillators, which normally interact and synchronize.

Sixteen oscillator neurons (the small and large neurons

[LNvs]) express a neuropeptide called pigment-dispersing

factor (PDF) whose signaling is often equated with M

oscillator output. The results present an unexpected PDF

receptor site; the large LNv cells appear to target a population

of non-neuronal cells that resides at the base of the eye.

Interleukin-15 (IL-15) is a cytokine produced in the normal

brain that acts on its specific receptor IL-15 R alpha and co-

receptors IL-2 R beta and IL-2 R gamma in neuronal cells

(38). The functions of the cerebral IL-15 system, however, are

not yet clear, that activation of hypothalamic neurons by IL-

15 in mice contributes to thermoregulation and metabolic

phenotype.

Age-related changes in circadian rhythms, including

attenuation of photic phase shifts, are associated with changes

in the central pacemaker in the SCN (39). Aging decreases

expression of mRNA for vasoactive intestinal peptide (VIP), a

key neuropeptide for rhythm generation and photic phase

shifts, and increases expression of serotonin transports and 5-

HT1B receptors, whose activation inhibits those phase shifts.

Studies showed that aging and chronic fluoxetine treatment in

hamsters decrease total daily wheel running without altering

the phase of the circadian wheel rhythm, in contrast to

previous reports of phase resetting by acute fluoxetine

treatment.

The circadian clock has a key role in physiological

adaption and anticipation of day/night changes (40). In

genetic screen for novel regulators of circadian rhythms,

mice lacking melanoma antigen family D1 (MAGED1)

exhibit a shortened period and altered rest-activity bouts.

These circadian phenotypes are proposed to be caused by a

direct effect on the core molecular clock network that reduces

the robustness of the circadian clock. In vitro and in vivo

evidence indicates that MAGED1 binds to nuclear receptors

to bring about positive and negative effects on clock genes.

Hence, novel circadian regulator, MAGED1, is indispensible

for the robustness of the circadian clock to better serve the

organism.

It is a long-standing view that circadian clock functions

proactively align internal physiology with 24-hour rotation of

the earth (41). Recent studies, delineate strikingly complex

connections between molecular network, coordinating a

diverse array of physiological processes to maintain dynamic

homeostasis. Brain-derived neurotrophic factor (BDNF) is a

cognate ligand for the TrkB receptor (42). BDNF and

serotonin often function in a cooperative manner to regulate

neuronal plasticity, neurogenesis and neuronal survival. NAS

(N-acetylserotonin) swiftly activates TrkB in circadian

manner and exhibits antidepressant effect in a TrkB-

dependent manner. Findings support the view that NAS is

more than a melatonin precursor, and that it can potently

activate the TrkB receptor.

Oscillator involvement

Mammalian circadian clock provides a temporal framework

to synchronize biological functions (43). To obtain robust

rhythms with periodicity of about a day, these clocks use

molecular oscillators consisting of two interlocked feedback

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loops. The core loop generates rhythms by transcriptional

repression via the periodic (PER) and cryptochrom (CRY)

proteins, whereas the stabilizing loop establishes roughly

antiphasic rhythms via nuclear receptors. Nuclear receptors

also govern many pathways that affect metabolism and

physiology. The core loop component PER2 can coordinate

circadian output with the circadian oscillator. PER2 interacts

with nuclear receptors including PPAR alpha and REV-ERB

alpha and serves as a co-regulator of nuclear receptor-

mediated transcription. Consequently, PER2 is rhythmically

bound at the promoters of nuclear receptor target genes

in vivo. In this way, the circadian oscillator can modulate the

expression of nuclear receptor target genes. The concept that

PER2 may propagate clock information to metabolic path-

ways via receptors adds an important facet to the clock-

dependent regulation of biological networks. Members of the

neuropeptide-Y (NPY) family acting via Y2 and/or Y4

receptors have been proposed to participate in the control of

ingestive behavior and energy homeostasis (44). Since these

processes vary between day and night, the circadian patterns

of locomotor, exploratory and ingestive behavior in mice with

disrupted gene for Y2 (Y2�/�) or Y4 (Y4�/�) receptors

were examined. The findings attest to a different role of Y2

and Y4 receptor signaling in the circadian control of

behaviors that balance energy intake and energy expenditure.

Effect of ethanol

Ethanol modulates the actions of multiple neurotransmitter

systems, including GABA (45). However, its enhancing

effects on GABA signaling typically are seen only at high

concentrations. In contrast, although GABA is a prominent

neurotransmitter in the circadian clock of the SCN, ethanol

modulation of clock phase resetting takes place at low

concentrations. A possible explanation is that ethanol

enhances GABAergic signaling in the SCN through activating

GABA(A) receptors that contain the delta subunit GABA (A

delta). Data support the hypothesis that ethanol acts on GABA

(A delta) receptors in the SCN to modulate photic and non-

photic circadian clock phase resetting. The data also reveal

distinct modulatory roles of different GABA (A) receptor

subtypes in circadian clock phase regulation.

Electrical effects

During the millennia, humans were exposed to electrical

fields which influenced various biochemical events. This

report deals with circadian clock interaction. Several earlier

reviews document the importance of electrical effects in

living systems (46–48).

Pulsed electromagnetic fields (PEMF) have proved effect-

ive in the prevention of osteoporosis both experimentally and

clinically (49). Circadian rhythm is as an essential feature of

bone metabolism. The findings might be helpful for the

efficacious use of PEMF mediations, evaluation of PEMF

action and experimental design in the future studies of

biological effect on electromagnetic fields. The effects of

different electromagnetic fields on some hematochemical

parameters of circadian rhythms in Sprague–Dawley rats were

investigated (50). Exposure to different electromagnetic fields

is responsible for the variations of some hematochemical

parameters in rats. The hypothetical relationship between

rhythm alterations and depression has prompted studies that

examine the resultant effects of various antidepressants (51).

Electroconvulsive therapy (ECT) exerts significant anti-

depressant effects that have been modeled in the laboratory

via the use of electroconvulsive shock (ECS) in rats. While

chronic ECS does alter the overt rhythms of motor activity

and temperature, it does not modify the functioning of

circadian pacemaker. The potential health risk of radio-

frequency electromagnetic fields (RF EMFs) emitted by

mobile phones are currently of considerable public interest

(52). A study investigated the effect of exposure to RF

radiation on steroid and pituitary hormone levels in healthy

males. Data show that the 900 MHz-EMF exposure does not

appear to affect endocrine function in men.

Suprachiasmatic nuclei

In mammals, an internal timekeeping mechanism located in

the SCN orchestrates a diverse array of neuroendocrine and

physiological parameters to anticipate the cyclical environ-

mental fluctuation that occurs every solar day (53).

Electrophysiological recording techniques have proved

invaluable in shaping our understanding of how this endogen-

ous clock becomes synchronized to salient environmental

cues and appropriately coordinates the timing of a multitude

of physiological rhythms in other areas of the brain and body.

A review discusses studies that have shaped our understand-

ing of how this biological pacemaker functions, from input to

output. Insights from studies indicate that, more than just

reflecting its oscillatory output, electrical activity within the

individual clock cell is a vital part of SCN clockwork itself.

Effect of melatonin

The circadian rhythm of the clock electroretinogram (ERG) is

regulated by melatonin (54). Data indicate that melatonin may

play a key role in regulating a day and night shift in the retina,

and does so via regulation of a retinal clock. An investigation

reveals that membrane electrical excitability is necessary for

free-running larval Drosophila circadian clock (55). Circadian

rhythms in human’s delta sleep electroencephalogram were

examined (56). Results suggest that the circadian pacemaker

contributes to determining the hours of day when one can

sleep deeply.

The suppression of melatonin by exposure to low-

frequency fields (EMFs) has been invoked as a possible

mechanism through which exposure to these fields may result

in an increased incidence of cancer (57). A review focuses on

the complexities associated with using melatonin as a marker

and the dynamic nature of normal melatonin regulation by the

circadian neuroendocrine axis. The amplitude of the b-wave

of the electroretinogram (ERG) varies with circadian rhythm

in the iguana; the amplitude is high during the day and low

during the night (58). The results suggest a negative feedback

loop involving dopamine and melatonin that regulates the

circadian rhythm of ERG-b-wave amplitude that is at least in

part generated in the brain.

Electromagnetic spectra reduce melatonin production and

delay the nadirs rectal temperature and heart rate (59).

Melatonin synthesis was completely suppressed by light, but

DOI: 10.3109/10799893.2013.822890 Cell signaling, receptors, electrical effects and therapy in circadian rhythm 271

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resumed thereafter. The nadirs of rectal temperature and heart

rate were delayed. The magnetic field had no effect. Infrared

radiation elevated rectal temperature and heart rate. Only

bright light affected the circadian rhythms of melatonin

synthesis, rectal temperature, and heart rate, causing a

dissociation, which might enhance the adverse effects of

shiftwork in the long run. Sensitivity to electromagnetic fields

was determined for altered circadian rhythms of heart

variability in patients with environmental intolerance (60).

Electromagnetic fields are different in the space environment,

especially in deeper space missions, such as moon or mars,

but their effects on human health have rarely been studied

(61). An article summarizes the current status of the

International Space Station project, studies circadian rhythm

and sleep in space and investigates electromagnetic fields.

The electric fish exhibits electric discharges rhythmicity both

in alternate light–dark and in constant dark conditions (62).

Evidence suggests that the electric discharge rhythm is under

control of the circadian clock. The report reveals the

relationship between electric discharge activity and the

circadian pacemaker.

Circadian rhythm and therapy

Melatonin

Melatonin is an important component of the avian circadian

system (63). A study investigates the effects of pinealectomy

and melatonin implantation on electroretinogram rhythms in

chicks. Results suggest that the circadian system regulates

rhythmic visual function in the retina, at least partially

through melatonin. The role played by the pineal gland and

melatonin may be specific to some physiological modalities

(e.g. vision) while not influencing others (e.g. feeding).

In patients with Alzheimer’s disease (AD), an irregular

day–night rhythm with behavioral restlessness during the

night makes a strong demand on caregivers and is among the

most important reasons for institutionalization (64). A

dysfunctioning circadian timing system is supposed to

underlie the disturbance or at least contribute to it. The

disturbance improves with increased environmental light,

which, through the retinohypothalamic tract, activates the

SCN, the biological clock of the brain. Because recent studies

have indicated both direct and indirect spinal projections to

the SCN, investigation was made of whether excitation of

spinal neurons by means of transcutaneous electrical nerve

stimulation could also improve circadian rhythm disturbances

in AD patients. The actigraphically obtained rest-activity

rhythm of 14 AD patients showed an improvement in its

coupling to Zeitbeber after transcutaneous electrical nerve

stimulation (TENS) treatment, but not after placebo treat-

ment. The daily time course of the electric potentials of the

hand skin and their asymmetry is different in healthy

volunteers and patients with essential hypertension (65).

The degree of the epidermis potential asymmetry depends on

the time of the day, is determined by the sympathoadrenal

activity, and is regulated by the central nervous system. Flies

that were exposed to uniform vertical 10 Hz electric square-

wave field changed the period length of their circadian

locomotor activity rhythm (66). Under constant condition, the

clock of short-period flies was slowed down by the field,

whereas the clock of the long-period flies was either affected

only scarcely or ran faster. The results are discussed with

respect to similar experiments on the effects of exposure to a

10 Hz field on the circadian system of man. A report deals

with the effect of electrical-stimulation of the optic nerves and

anterior optic chiasm on the circadian activity rhythm of the

Syrian-hamster (67).

The circadian rhythm of melatonin production in the

mammalian pineal gland is modified by visible portions of the

electromagnetic spectrum, i.e. light, and reportedly by

extremely low-frequency electromagnetic fields, as well as

by static magnetic field exposure (68). Static magnetic fields

have been repeatedly shown to perturb the circadian mela-

tonin rhythm. The retinas, in particular, have been theorized

to serve as magnetoreceptors with the altered melatonin cycle

being a consequence of a disturbance in the neural biological

clock, i.e. the SCN of the hypothalamus, which generates the

circadian melatonin rhythm. The disturbances in pineal

melatonin production induced by either light exposure or

non-visible electromagnetic field exposure at night appear to

be the same, but whether the underlying mechanisms are

similar remains unknown.

Asthmatic post-menopausal women treated with glucoster-

oids show lowered circadian secretion of melatonin as a

consequence of lowering its secretion at nocturnal hours.

Hormonal replacement therapy causes a decrease of

daily melatonin secretion in healthy, as well as asthmatic

women, not disturbing circadian rhythm of this hormone’s

secretion (69).

The circadian rhythm of heart rate variability is present in

normal subjects and in patients with angina. With beta-

adrenergic blockade, significant improvement occurs in all

daytime domain parameters (70). A report deals with

improvement of circadian rhythm of heart rate variability by

eurythmy therapy training (71). There is an article on nocturia

due to the reversal of circadian rhythm on long-term steroid

therapy (72). Light therapy normalized temperature circadian

rhythm in patient with eating disorders (73). The light therapy

can also contribute to the improvement of pathological eating

pattern, because of the functional connections between light

and food entrained oscillators. The light may also help to

restore the irregular circadian rhythmicity induced by chaotic

food intake. The acrophases of hot flashes and elevated

activity levels may represent a normalization of circadian

rhythms following androgen deprivation therapy (74).

Evidence was provided indicating that beta blocker therapy

modifies circadian rhythm acute myocardial infarction (75).

Results suggest that morning administration of bright light

may protect women from experiencing circadian rhythm

deterioration during chemotherapy (76). An article assessed

the efficacy of gene therapy in mice using photoentrainment

of circadian rhythm (77).

Sleep disorders and jet lag

Circadian rhythm sleep disorders (CRSD) are due to the

misalignment between the timing of the endogenous circadian

rhythm and the desired or socially acceptable sleep–wake

schedule, or dysfunction of the circadian pacemaker and its

afferent/efferent pathways. CRSDs include delayed sleep

272 P. Kovacic & R. Somanathan J Recept Signal Transduct Res, 2013; 33(5): 267–275

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phase disorder, advanced sleep phase disorder, non-24-hour

sleep-wake disorder, irregular sleep–wake rhythm disorder,

shift work disorder and jet lag disorder (78). A review deals

with these circadian-related disorders (78). A report suggests

light is the strongest entraining agent of circadian rhythms

and timed exposure to bright light is often used in the

treatment of circadian rhythm sleep disorders. In addition,

timed administration of melatonin, either alone or in

combination with light therapy, has been shown to be useful

in the treatment of the following circadian rhythm sleep

disorders: delayed sleep phase, advanced sleep phase, free-

running, irregular sleep wake, jet lag and shift work (78).

A recent review also deals with the therapeutic application of

melatonin for the management of circadian rhythm-related

sleep disorders, shift work and jet lag (79).

Central nervous system

Alzheimer’s disease (AD) is characterized by a progressive

loss of memory and cognitive function, and by behavioral and

sleep disturbances, including insomnia (80). The pathophysi-

ology of AD has been attributed to oxidative stress-induced

amyloid-b-protein deposition. Abnormal tau protein, mito-

chondrial dysfunction and protein hyper-phosphorylation

have been demonstrated in neural tissues of AD patients

(80). Melatonin and a number of melatonin agonists, such as,

ramelteon, agomelatine and tasimelteon, are used clinically

for treating insomnia and other sleep disorders and the same

drugs may be beneficial in treating AD (81–83). A study also

revealed ‘‘chronobiotic’’ administration of melatonin

improves sleep quality and cognitive performance in early

AD patients (84,85). More data are emerging demonstrating

how CLOCK gene system might contribute to pathophysi-

ology of Alzheimer’s disease and other forms of dementia

(86). A review deals with therapeutical potential of melatonin

and its analogs in Parkinson’s disease (87).

Conclusion

Cell signaling, receptors, therapy and electrical effects are

widely involved in the biological domain. This review

provides involvement with circadian rhythm. There are

unifying mechanistic aspects comprising free radicals. The

multifaceted approach can also be applied to the circadian

clock in the biological domain.

Acknowledgements

Editorial assistance by Thelma Chavez is acknowledged.

Declaration of interest

The authors report no conflicts of interest. The authors alone areresponsible for the content and writing of this article.

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