Make no mistakes about MTHFR and brain function

Keep Methylation Central

To understand attention, attention based learning, motivation, pleasure, and the other functions of the neurotransmitter dopamine, you have to know something about D4 dopamine receptors. And critical to the function of dopamine receptors is the MTHFR C677T gene and enzyme.


The function of the D4 dopamine receptor depends upon the cell membrane in which they are embedded. 

The membrane surrounding your cell, the plasma or cell membrane, is represented above by a three dimensional fluid mosaic. It is composed of a bi-lipid layer, a double layer of lipid or fat, which has a head at one end. The lipid is actually phospholipid.

Nerve cells also have a phospholipid cell membrane. In this depiction, the head is represented by the red, green, purple, and lime green rounded structures. Anyone who has listened to the Tuesday night calls has heard me talk about phospholipids at length.

Phosphatidyl serine complex is the important shortcut support that almost everybody starts out on. It is a complex of the same phospholipids in the nerve cell wall.

Receptor sites are positioned in the cell membrane. They are represented by pink lobed molecules with antenna-like structures projecting out of them. The antenna-like structures grab the appropriate molecule for the type of receptor involved and transport it into the cell.

The cell membrane must be fluid. It can’t be rigid. If it is too rigid, the molecules in the membrane can’t move or function properly. They need to be able to move in order to signal appropriately.

Some receptors function by totally inverting into the cell. They invert and pull the substance into the cell by doing so. You cannot have a stiff, inflexible cell membrane and do this effectively. That is what is wrong with trans fats: they are too stiff.

The receptor I am focusing on today is the D4 dopamine receptor. Dopamine is the neurotransmitter responsible for attention, motivation, pleasure and reward motivated behavior. It is an extraordinarily important neurotransmitter because it is the predominant neurotransmitter in your pre-frontal cortex.

Cognitive behavior is processed in your pre-frontal cortex. It is where your executive function resides. It’s the brain power you use to cross the street, the mental apparatus that you need to make decisions. It’s the seat of your personality, the home of all the characteristics that make you you.

The D4 dopamine receptor is responsible for attention and attention initiated learning. It operates by inverting into the cell. A very fluid cell membrane is necessary to do this. Without this fluidity, you may get a diagnosis of Attention Deficit Disorder or Attention Deficit Hyperactivity Disorder.

Dopamine activation of the D4 receptor initiates a cycle of phospholipid methylation. There is actually a methionine cycle which produces methyl groups attached to this dopamine receptor.



Depicted above is the bi-lipid layer of the phospholipid cell membrane. The oval structure is a representation of a receptor site which is made of protein.

On the left side, there is no phospholipid methylation. There are no methyl groups between the heads of the molecules in the membrane.

When there is a space made by the methyl groups between the phospholipid heads, there is more room for the receptors to be able to move and function. It is a more fluid membrane. The protein receptor will be able to move around better and will be able to signal and react with other proteins more easily.

Inadequate methylation negatively impacts your ability to attend and learn. The dopamine receptor needs to be able to reconfigure itself. It needs to be able to invert itself into the cell and then come back out again. It is not able to do that if the membrane is inflexible. 

Phospholipid methylation, the addition of a methyl group to phospholipids, reduces the packing density of the membrane and enhances the activity of embedded, integral membrane proteins like the D4 receptor.

The D4 receptor has a methylation cycle associated with it. The activity of this methylation cycle is affected by the availability of 5 methyl tetrahydrofolate (5 MTHF). When the level of 5 MTHF is decreased, it becomes a limiting factor. The receptors wait for a new methyl group to start the activation. Receptors sitting around waiting for methyl groups greatly reduces the impact of any dopamine present. Even very high amounts of dopamine that may be present will not activate the receptor if there is too little 5 MTHF.

And what determines 5 MTHF availability? The function of MTHFR gene and the enzyme for which it encodes. These are critical for an adequate supply of 5 MTHF. MTHFR 3 is even a more profound genetic down regulation of enzyme activity than MTHFR C677T. So proper function of MTHFR or appropriate supplementation of 5 MTHF are necessary for the function of dopamine which is critical for good brain function. 

There is more information on methyl groups and methylation on my web site at and on my blog at

My Tuesday night call is your chance to learn what you need to know to get this important area of your life and biochemistry under control. I take your questions on many topics, among them the impact of your personal genetics on your biochemistry. I discuss how to balance your biochemistry with nutritional supplements that bypass problem genetics.

It is up to YOU to learn about treating psychiatric and other chronic illness successfully.

You need to know about the role of optimizing both methyl group production and your capacity for methylation.
This is your opportunity.

Dr. Mullan would like to invite you to her Open Forum which is held on Tuesday night at 5:00 PM Pacific Time (8:00 PM Eastern Daylight Time, 7:00 PM Central, 6:00 PM Mountain) in order to answer your questions and introduce you to her work. You may be checking her out to see if you would like to consult her. Or you may not have the option of working with her, but would still like to get her information.

The call in number is (605) 562-3140, and the access code is 691392#. 

When you hear Dr. Mullan come on the line, press *6 to get into the question and answer line if you have a question.

This program is not recorded.  International call in numbers are linked here.


Thank you for your interest in Dr Mullan’s work.

Nancy Mullan MD
Author, lecturer, clinician
Dr. Nancy Mullan is best known for her natural treatment of chronic illness, including Autism Spectrum Disorders, Lyme and MTHFR+.
2829 Burbank Blvd., Suite 202, Burbank, CA  91505
T: (818) 954-9267 – F: (818) 954-0620



About Nancy Mullan, MD

Some people call Dr. Nancy Mullan the MTHFR genetic medicine expert. Dr. Mullan works with people who are struggling with chronic disease or other significant illness, who are willing to use diet and genetics-based nutritional supplementation, and who want to increase wellbeing and energy, enhance immunity, lift mood, fine-tune genetic function, and get their lives back. Dr. Mullan has studied at a number of exceptional institutions: the University of Pennsylvania, Tufts University School of Medicine, and the University of Chicago Hospitals and Clinics. She excels at integrating the results of biochemical and genetic testing into sustained clinical improvement for you. She has succeeded with patients who confounded the specialists at Massachusetts General Hospital, the Mayo Clinic, the Cleveland Clinic, Stanford, and many well-known integrative medical doctors. When recommending her, her patients say, “This is the woman you need to talk to. She really knows how to handle tough clinical problems.” Dr. Mullan's specialty areas are MTHFR+, methylation genetics, and genetics-based nutritional supplementation. Within this context, she most often works with Chronic Fatigue Syndrome, Lyme Disease, Psychiatric Disorders, Autism Spectrum Disorders, Women’s Health Issues, Thyroid Disorder, Gastrointestinal Disorder, and Heavy Metal Toxicity.
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