Is the M3 Receptor a Target for Obesity Drug Development?

Acetylcholine (ACH) is a key neurotransmitter involved in modulating a variety of central and peripheral nervous systems.  ACH acts on two types of receptors-nicotinic receptors and muscarinic receptors.  There are at least 5 submits of the muscarinic receptor (M1 through M5).  Each receptor appears to have specific functions.

Knockout mice (mice with absence of a specific gene) can provide some insight into the function of individual neurotransmitter receptors.  But translating mice findings into humans is complicated.  A recent study by Pomper et al published in the journal Neurology provided a unique analysis of a man felt to have a specific deficiency of the M3 receptor.

A 38 year old man presented for assess with the following signs and symptoms:

• Big pupils (mydriasis) unresponsive to light
• (Pupil size and responsive appeared normal in photos of patient at age 18)
• Reduce ability to empty his bladder (external pressure only method of voiding)
• Recurring bladder infections related to incomplete bladder emptying
• Lean body habitus (BMI 18.5)
• Impaired sweating function with dry hands and feet

These symptoms were consistent with findings of mice with absent M3 receptors following genetic manipulation.  These mice typically are lean with pupil size abnormalities with limited response to ACH agonist drugs such as pilocarpine.  M3 knockout mice also show bladder function abnormalities.

Specific deficiency of the M3 receptor protein was found in testing of this case study.  The authors examined this man for genetic abnormalities involving the M3 receptor and were unable to find an abnormality.  However, the man showed high levels of auto antibodies of no specific pattern.  Anti-nuclear antibodies found in Sjogren syndrome were not present.  The authors note that patients with Sjogen syndrome have symptoms suggestive of M3 receptor dysfunction including impaired sweating.

The intriguing finding in this man to me was the lean body habitus.  We know that anticholinergic drugs such as Benadryl (diphenhydramine) when used over extended periods of time can cause increased appetite and weight gain.  It is possible that drugs designed to decrease M3 receptor activity may have potential in the treatment of obesity.  However, it is likely such drugs would have effects on bladder and ocular function.


Drug model of muscarine, the muscarinic receptor agonist, courtest of Creative Commons, author RingO 

Pomper JK, Wilhelm H, Tayebati SK, Asmus F, Schüle R, Sievert KD, Haensch CA, Melms A, & Haarmeier T (2011). A novel clinical syndrome revealing a deficiency of the muscarinic M3 receptor. Neurology, 76 (5), 451-5 PMID: 21282591