1) Barbiturates are central nervous system depressants that act as sedatives, hypnotics, and anticonvulsants by enhancing the effects of the inhibitory neurotransmitter GABA at GABA-A receptors. 2) Chloride channels are a diverse family of ion channels that transport chloride ions across cell membranes. They play important roles in processes like neuronal excitability, muscle function, and transepithelial salt transport. 3) The document discusses the mechanisms of action and adverse effects of barbiturates, summarizes research on chloride channel families including CLC channels, and references additional sources for more information.

1. Physiology Project
Kazan State Medical
University
By : Mahi

2. Barbiturates
and
Chloride channel
By : Mahi

3. Barbiturates
• Barbiturates are drugs that act as central nervous system depressants.
• They are also effective as anxiolytics, hypnotics, and anticonvulsants.
• Barbiturates vs. Benzodiazepines.
• Both these highly addictive classes of drugs are medically prescribed to
treat insomnia, anxiety, and in some cases seizures.
•Derivatives of Barbituric acid or Malonylurea: Combination of urea and
malonic caid
•Depressants of the central nervous system, impair or reduce activity of
the brain by acting as a Gamma Amino Butyric Acid (GABA)
potentiators
•Produce alcohol like symptoms such as ataxia (impaired motor control),
dizziness and slow breathing and heart rateBy : Mahi

4. Barbiturates were widely diverted from
medical use and used on the street in
the 60s where they were called
“downers” and sold under a variety of
different names.
Illicit use has declined as medical use
has declined.
They had a low therapeutic index and
were often used for suicide.
Marilyn Monroe died of
barbiturate overdose in 1962
Barbiturates: History
By : Mahi

5. Mechanism of Action
GABA binding site
Barbiturate binding site
Barbiturates potentiate the effect of GABA at the GABA-A receptor.
The GABA-A receptor is a ligand gated ion channel membrane receptor
that allows for the flow of Cl through the membrane in neurons.
GABA is the principle neurotransmitter for this receptor which upon
binding causes the channel to open and creates a negative charge in
the transmembrane potential.
This makes it an Inhibitory neurotransmitter
GABA
By : Mahi

6. Mechanism of Action
Barbiturates potentiate the effect of GABA by binding to the GABA-A receptor at
a nearby site and increasing the chloride flow through the channel.
Barbiturates also block the AMPA (2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)
propanoic acid) receptor which is sensitive to glutamate, the excitatory
neurotransmitter.
Glutamate performs the opposite effect from GABA restricting ion flow and
increasing the transmembrane action potential of the neuron.
By blocking this action Barbiturates serve to increase the duration of the
receptor response to GABA and extend the depressed condition of the cell.
By : Mahi

7. •Treatment of INSOMNIA
• Phenobarbitone for EPILESPY
• Thiopentane for ANAESTHESIA
• Adjuvants in psychosomatic disorders
• Pre-operative sedation
• Treatment of seizure disorder
USES -
BARBITURATES
By : Mahi

8. Prolongs inhibitory
actions of GABA
Increases
duration of
ionophone
opening
Enhance
GABA
mediated Cl
currents
Mechanism
Of Action
By : Mahi

9. BARBITURATES ~ adverse
effects
• Residual depression after the main effect of drug
has passed
• Paradoxical excitement
• Hypersensitivity reaction – localized swelling of
eyelid, cheek, or lip, erythematous or exfoliative
dermatitis
• Synergistic action with ethanol and
antihistamines
By : Mahi

10. BARBITURATES ~ TOXIC
EFFECTS
• Slurred speech, ataxia, lethargy, confusion, headache,
nystagmus
• CNS depression, coma, shock
• Pupils first constrict and then dilate because of hypoxia
• hypothermia
• Cutaneous bullae
• Death due to respiratory arrest of cardiovascular collapse
• Chronic abuse  tolerance.
• Withdrawal reaction: anorexia, tremor, insomnia,
cramps, seizures, delirium, orthostatic hypotension
By : Mahi

11. Chloride
Channel
By : Mahi

12. •Chloride channels are a functionally and
structurally diverse group of anion selective
channels involved in processes including the
regulation of the excitability of neurones, skeletal,
cardiac and smooth muscle, cell volume regulation,
transepithelial salt transport, the acidification of
internal and extracellular compartments, the cell
cycle and apoptosis.
By : Mahi

13. Chloride channels are a superfamily of poorly
understood ion channels specific for chloride. These
channels may conduct many different ions, but are
named for chloride because its concentration in vivo is
much higher than other anions.[1] Several families
of voltage-gated channels and ligand-gated channels
By : Mahi

14. A picture representation of
a CLC chloride channel.
The arrows indicate the
orientation of each half of
the individual subunit.
Each CLC channel is
formed from two monomers,
each monomer containing
the antiparallel
transmembrane domain.
Each monomer has its
own pore through which
chloride and other anions
may be conductedBy : Mahi

15. A cartoon representation
of a CLC channel monomer.
Two of these subunits
come together to form the
CLC channel.
Each monomer has three
binding sites for anions,
Sext, Scen, and Sint.
The two CBS domains
bind adenosine nucleotides
to alter channel function
By : Mahi

16. Cellular Cl signaling. Cells actively transport Cl
across the plasma membrane by transporters
that accumulate Cl intracellularly or extrude it
from the cell. Cl flows passively across a variety
of Cl channels in the plasma membrane,
including Ca-activated Cl channels (CaCC),
cAMP-activated Cl channels (CFTR), cell volume-
regulated anion channels (VRAC), CLC voltage-
gatedCl channels, and ligand-gated anion
channels. In addition, Cl channels and
transporters are found in intracellular
membranes, such as the endosomal-lysosomal
pathway, and play a role in regulating
intravesicular pH and Cl concentration. Many
proteins are regulated by Cl, as depicted by the
Cl-binding protein.By : Mahi

17. 1- A, top: CLC Cl− channel model based on biochemical
analysis. Conflicting results exist in the D4/D5 region.
The broad hydrophobic region between D9 and D12 was
difficult to investigate experimentally, but it was clear that
it has an odd number of membrane crossings.
The carboxy terminus of all eukaryotic CLC proteins has
two CBS domains that have a so far unspecified role in
protein-protein interaction.
ClC-K proteins associate with the β-subunit barttin,
which spans the membrane twice.
A,bottom: model of CLC Cl− channel derived from three-
dimensional crystal structure of a bacterial CLC protein
shows that the membrane-associated part of the protein is
composed of 17 α-helices (helix A is not inserted into the
membrane).
Inspection of the crystal reveals that most of these
helices are not perpendicular to the membrane, but
severely tilted.
Topology models for the established Cl− channel families
By : Mahi

18. Many of these helices do not span the width of the
bilayer.
This even serves an important function, as Cl− is
coordinated in the pore by helices extending from either
side of the membrane into the center plane.
For comparison and reference, the previous
nomenclature of CLC domains (D1–D12) is indicated by
shaded areas and dashed lines.B: topology model of cystic
fibrosis transmembrane conductance regulator (CFTR), a
member of the ABC transporter superfamily.
It has two blocks of six putative transmembrane
spanning domains each, which are separated by a
cytoplasmic region that contains the first nucleotide
binding fold (NBF1) and the regulatory R domain.
A second NBF is present in the carboxy terminus. It is
not yet firmly established whether CFTR functions as a
monomer or as a dimer.C: topology model of ligand-gated
anion channels.
These proteins have four transmembrane domains and
assemble to homo- and heteromeric pentameric channels.By : Mahi

19. Transepithelial transport models. A: potassium secretion in the stria vascularis of the cochlea needs basolateral
Cl−channels for recycling Cl− that is transported into the cell by a Na+-K+-2Cl− cotransporter (NKCC1). K+ is secreted apically
via KCNQ1/KCNE1 potassium channels. The basolateral membrane most likely contains parallel heteromeric ClC-
Ka/barttin and ClC-Kb/barttin Cl− channels (147). Mutations in KCNQ1, KCNE1, NKCC1, and BSND (encoding barttin)
cause deafness, but mutations in either ClC-Ka or ClC-Kb alone do not. B: chloride reabsorption in the thick ascending limb
of Henle's loop involves an apical Na+-K+-2Cl− cotransporter (NKCC2) that needs a parallel K+ channel (ROMK1, Kir1.1) for
recycling potassium. Cl− leaves the cell passively across the basolateral membrane through the ClC-Kb/barttin Cl−channel
(147). Mutations in NKCC2, ROMK, or ClC-Kb cause variants of the same disorder, Bartter's syndrome. Mutations in the β-
subunit barttin (BSND) cause Bartter syndrome with deafness, as its loss of function affects both ClC-Ka and ClC-Kb.C:
chloride secretion in intestinal crypt cells. Intracellular Cl− concentration ([Cl−]i) is raised above equilibrium by a Na+-K+-
2Cl− cotransporter that needs a parallel K+ channel (KCNQ1/KCNE3) for recycling and passively leaves the cell via the
apical cAMP-stimulated Cl−channel CFTR. By : Mahi

20. Families of chloride Channels
By : Mahi

21. • The CLC family of Cl− channels in mammals. Based on homology, the nine
mammalian CLC proteins can be grouped into three branches, as shown by the
dendrogram (left).
• Channels of the first branch predominantly reside in the plasma membrane,
whereas channels from the two other branches are thought to be predominantly
intracellular.
• The localization on human chromosomes is indicated below the channel names.
• The next columns indicate the most important features of their tissue distribution,
their presumed functions, the phenotype of the corresponding knock-out (KO)
mouse model, and the name of the human disease associated with the channel,
respectively.
• The asterisk indicates that mutations in barttin, a β-subunit for ClC-Ka and ClC-Kb ,
cause Bartter syndrome with sensorineural deafness and kidney failure because it
compromises the function of both ClC-Ka and ClC-Kb in the kidney and the inner
ear.
By : Mahi

22. The double-barreled structure of CLC channels. A: a simple model of a CLC channel.
As best exemplified by theTorpedo channel ClC-0, CLC channels are believed to be dimers
that have two largely independent pores.
These pores can be gated individually or can be closed together by a common gate. In ClC-
0, both pores have identical properties, and their individual gates are independent.
B: single-channel recordings supporting the double barrel model. Top: a recording from a
native ClC-0 channel incorporated into a lipid bilayer.
Note that there are long periods with zero current flow, attributed to a closed slow gate
that closes both pores.
An opening of this gate leads to “bursting” activity in which the equally spaced
conductance levels of the individual pores become apparent. (From Miller C and Edwards
EA.Chloride Channels and Carriers in Nerve, Muscle, and Glial Cells, edited by Alvárez-Leefmans
FJ and Russel JM. New York: Plenum, 1990, p. 383–420.) Middle: excised patch containing a
concatemer of a wild-type (WT) and a mutant (S123T) ClC-0 protein.
Note that the recording can be explained by a large pore with WT conductance and a
small mutant pore.
In the recording to theright, bromide was substituted for chloride. As known for homomeric
WT and mutant channels, WT ClC-0 conducts Cl−better than Br−, but this selectivity is lost in the
mutant.
This is faithfully reflected in the concatemer, showing that the permeation properties of
both pores are independent. [From Ludewig et al. Bottom: registration of a ClC-0/ClC-2
concatemer. The recording can be explained by a ∼8.5 pS ClC-0 pore attached to a ∼2.5 pS ClC-2
pore. These values correspond to those of the corresponding homodimers, arguing even more
strongly that pores are formed within the individual subunits.
By : Mahi

23. By : Mahi

24. • Proximal tubular defect in endocytosis leads to secondary changes in calciotropic hormone levels and to
phosphaturia in ClC-5 KO mice.
• A: mechanism leading to phosphaturia. Parathyroid hormone (PTH) is filtered into the primary urine across the
glomerular filter (left). It can bind to megalin (symbolized by the zig-zag sign), which leads to its internalization
and degradation in lysosomes.
• The reduced endocytosis (symbolized by hyphens) leads to an increased concentration of PTH in later parts of the
proximal tubule compared with wild-type mice. This leads to an increased binding to apical PTH receptors (Y),
stimulating the endocytosis of apical Na+-Pi cotransporters and their degradation in lysosomes.
• This leads to the phosphaturia observed inClcn5 − mice and in human patients with Dent's disease. B: mechanism
leading to changes in vitamin D metabolism. As shown in A, the defect in endocytosis entails a luminal increase in
PTH concentration, resulting in enhanced PTH signaling.
• This increases the transcription of α-hydroxylase, a mitochondrial enzyme that converts 25-hydroxyvitamin
D3[25(OH)D3] to the active hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. On the other hand, the precursor
25(OH)D3, bound to its binding protein, is filtered into the primary urine and is normally endocytosed via megalin.
• This constitutes the main supply of 25(OH)D3 for the α-hydroxylase, reducing the availability of the substrate in
the knockout. The supply of 25(OH)D3 is further compromised by a severe loss of this precursor into the urine
that may lead to decreased serum level.
• Thus the impaired endocytosis leads to two opposing effects on the synthesis of 1,25(OH)2D3: a decrease in the
precursor and an increase in enzymatic activity.
• The relative strengths of these effects determine whether there will be an increase or decrease in the serum
concentration of the active hormone. An increase will lead to increased intestinal Ca2+ reabsorption and,
secondarily, increased renal Ca2+ secretion, eventually causing kidney stones.
By : Mahi

25. Family of ligand-gated
chloride channels.
The dendrogram shows 19
members of the GABA
receptor and 4 members of
the glycine receptor family
and their chromosomal
localization.
No human ortholog for
the ρ3-subunit has been
identified.
The chromosomal
localization of the π-subunit
is not known. By : Mahi

26. • http://physrev.physiology.org/content/82/2/503.long
• https://www.emory.edu/HEARTCELL/
• https://en.wikipedia.org/wiki/Chloride_channel
• http://physiologyonline.physiology.org/content/20/5/292
• https://www.ncbi.nlm.nih.gov/pubmed/11917096
Reference
By : Mahi

27. Name :
Group :
Thank You Very Much
By : Mahi