Carbon Monoxide in signal transduction

Presenter: Dr. Karthikeyan P

Moderator: Dr. B. C. Koner

Brief history of toxic CO

➢Greek & Roman times - Used for execution

➢1857 - Claude Bernard first described the mechanism of toxicity of CO

➢1927 - effect of CO on tissue uptake of O2 was demonstrated by warburg

Sources of carbon monoxide

Vehicular & industrial pollution

Cigarette & household smoke

Incomplete combustion of organic fuel

Exogenous sources

Mechanism of toxicity

➢200 times more affinity for Hb than O2.

➢ODC shifted to left.

➢Decreases function of cytochromes.

CO toxicity

➢Colorless, odorless gas not detected by human senses.

➢Low conc - cardiovascular and neurobehavioral effects

➢High conc - coma and death

➢Treatment: hyperbaric O2. (Haldane 1895)

Brief history of neurotransmitter CO

➢Described role of NO, CO, D-serine

Solomon H. Snyder

Brief history of messenger CO

1952 - Sjöstrand reported the endogenous synthesis of

CO.

1968 – Heme oxygeanse was identified.

Mid 1980 - HO-1 and HO-2 isoforms were discovered.

1993 - role of CO as neurotransmitter by Verma et al.

1997 - HO-3 was discovered.

The 1998 Nobel Prize in Physiology or

Medicine

Nitric oxide as a cell signaling molecule

GASOTRANSMITTER

I. Small molecule of gas

II. Freely permeable to membranes. Effects do not rely on the membrane receptors.

III. Endogenously and enzymatically generated and its production is regulated

IV. Has well defined and specific functions at physiologically relevant concentrations

V. Functions of this endogenous gas can be mimicked by its exogenously applied counterpart

VI. its cellular effects may or may not be mediated by second messengers, but should have specific cellular and molecular targets

Differences from classical neurotransmitters

Classical neurotransmitters Gaseous neurotransmitters

Synthesized and stored in vesicles

Synthesized fresh and not stored

Act via receptors like muscarinic, nicotinic etc.

Too small to have receptors. Directly diffuse across cell membrane and act on molecules.

e.g: Ach, epinephrine etc e.g: CO, NO, H2S

Sources of carbon monoxide

Photo-oxidation, xenobiotics

Lipid peroxidation

Product of heme catabolism

Production of CO by cyt P450 during iron-dependent lipid peroxidation.

Toxicol In Vitro. 2002 Feb;16(1):1-10.

Synthesis of CO

3 isoforms of HO

➢HO1 (inducible) [ch.22] - found in many tissues like lungs, spleen etc.

➢HO-2 (constitutive)- found in brain, neurons in GIT, blood , testes

➢HO3 - ? Retrotransposition of HO-2 (No introns)➢ does not have potent enzymatic activity

Targets of CO

➢Soluble Guanylyl cyclase (sGC)

➢ Ion channels

➢K+ Channels (KCa and KATP)

➢Na+ channels

➢Ca2+ channels

➢Hemoprotein targets and others

BK Channel

Name of Protein Effects of CO or HO Up-Regulation

Catalase Inhibition

Cyclooxygenase Inhibition & activation

Cytochrome c Binding

Cytochrome P450 Inhibition

Cytochrome c oxidase Inhibition

Guanylyl cyclase ActivationHemoglobin Inhibition

Neuroglobin Inhibition

Myoglobin Inhibition

Cytoglobin Inhibition

NADPH oxidase Inhibition

NO synthases Inhibition

Peroxidases Binding

Prostaglandin H synthase Binding

Tryptophan dioxygenase Inhibition

NPAS2 Inhibition

Physiological roles

➢Circulatory system – vasorelaxation, acts in concert with NO

➢Urogenital system - Plays a role in micturition

➢In the nervous system:

➢Odor response

➢Vision

➢Hearing

➢Thermal regulation

➢Nociception

➢Chemoreception

➢LTP, memory

Physiological role

Hormones

➢Mediates release of GnRH, Neuropeptide Y from hypothalamus.

➢Release of Insulin from islets of Langerhans.

Neuromuscular junction

➢The presence of HO-2 immunoreactivity in the rat neuromuscular junction suggests that it may act as a post and pre-synaptic neurotransmitter in the NMJ.

Physiological role

Circadian rhythm

➢CO acts on NPAS2, a mammalian transcription factor that regulates circadian rhythm.

➢ It has also been linked to the suprachiasmatic nucleus in the brain.

➢CO has got anti-inflammatory (acts on COX) and anti-

apoptotic activities. These activities can be exploited in

preventing graft rejection.

Cotransmission with NO

CO and NO act together additively in the

➢ Gastrointestinal system

➢ Nervous system

➢ Genitourinary system

Many of the functions of NO are dependent upon the presence of CO.

Target of NO & CO

Comparison between NO & CO

Exclusively on the endoplasmic reticulum

Dendrites, axons, endoplasmic reticulum, and cytosol

Subcellular localization

HO1 - inducible HO-2 - constitutive

iNOS - inducible nNOS, eNOS -constitutive

Gene isoforms

Catalyzes a mixed oxidation of heme to form the inert diatomic gas, CO.

Catalyzes a mixed oxidation of arginine to form the diatomic gas radical, NO.

Biosynthesis

HO-2nNOS

Nonadrenergic, noncholinergicneurotransmitter, most prominently in the internal anal sphincter

Nonadrenergic, noncholinergicneurotransmitter, most prominently in the pylorus

Role in GIT

Like eNOS and nNOS, HO-2 is present in both the endothelium and the surrounding adventitial neurons.

Other targets?

Soluble guanyl cyclase

Protein kinase C

HO-2

Originally discovered as EDRF

Can directly alter protein function by S-nitrosylation.

Soluble guanyl cyclase

Calcium/calmodulin

nNOS

Role in blood vessels

Activation

Activation of HO-2 protects against toxicity by quenching free radicals.

Activation of nNOSaugments toxicity by generation of a free radical.

Neurotoxicity

HO-2nNOS

Pathophysiology

Neurodegeneration and brain disorders

➢HO/CO system has been implicated in various neurodegenerative diseases like

➢ Alzheimer's disease

➢ Parkinson's disease

➢ Amyotrophic lateral sclerosis

➢This system has also been found altered in seizuredisorders.

Pathophysiology

CO in cardiovascular pathophysiology

➢Hypertension

In hypertension CO/HO system plays a role in following conditions

➢Hypertension induced by HO inhibitors

➢Spontaneously hypertensive rats

➢Salt induced hypertension

➢Angiotensin-II induced hypertension

➢Renovascular hypertension

➢Portal hypertension

➢Cardiac hypertrophy and heart failure

Pathophysiology

In addition role of CO/HO system can be traced to disorders like

➢Neurotoxicity

➢Genitourinary diseases

➢GIT disorders

Pathophysiology

➢ Carbon monoxide in transplantation

➢Survival of Allograft

➢Survival of Xenograft

➢ Carbon monoxide in apoptosis and cell proliferation➢ Vascular smooth muscles

➢ Endothelial cells

➢ Other types of cell

Perspectives

• Prevention of graft rejection

• Anti inflammatory agent

• Treatment of hypertension and lung diseases.

• Treatment of diseases of urogenital system.

• Treatment of GI diseases (Irritable bowel syndrome)

H2S

•Produced by CBS in brain & CGL in smooth muscle

•Produced in response to neuronal excitation

•Alters hippocampal long-term potentiation

•Regulate the release of corticotrophin-releasing hormone from hypothalamus