The Nicotinic Cholinergic Genes (16)

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The reader will recall from our earlier discussion that there are two categories of nicotinic cholinergic receptor genes – the CHRNAs and the CHRNBs, corresponding to the α and β receptors, respectively. Broadly, the CHRNAs have been repeatedly tied to lung cancer[1][2][3] and other lung diseases such as chronic obstructive[4][5] pulmonary disease and asthma[6][7][8], though always in the context of smoking[9][10]. They have also repeatedly been tied to substance use and addiction[11]. A single gene, CHRNA7, has also been linked to schizophrenia[12] and identified as a potential target for antipsychotic drugs[13], which explains why the α7 receptor-agonizing compound SEN12333 is being studied for the treatment of schizophrenia. But why the strong ties to cancer and lung disease?

Nicotinic cholinergic receptors bind to nicotine as well as 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN), the cancer causing derivates of smoking. The nAChRs are also in the lungs, where they bind to both nicotine and NNK and NNN. Disturbingly, NNN, bacon, and processed meats are all nitrosamines, making NNN a carcinogen even when not burned. Moreover, it has an affinity for the nicotinic receptors that is 5,000x times greater than nicotine.

NNK is also found in unburned tobacco and has an affinity for the α7 receptor (the one tied to schizophrenia) that is 1,300x greater than nicotine’s affinity. It is a mutagen that causes polymorphisms in the human genome, such as at the angiotensin II (AT2) gene that is a target of blood pressure medications. Interestingly, cruciferous vegetables and green tea’s EGCG have been shown to inhibit damage arising from NNK.

Nonetheless, the nicotinic cholinergic genes are found at central regulatory loops for numerous cell growth pathways and may act as oncogenes (i.e. cancer promoting genes) at various steps in the developments of tumors[14], from the practice of smoking tobacco.


In terms of addiction, the nAChR genes have been associated with the habitual use of nicotine, alcohol, cocaine, and opioids. These drugs affect the GABAergic, dopaminergic, and serotonergic systems, and the nAChR’s genes influence over them is indicative of the exceptional crosstalk that the nicotinic cholinergic receptors share with other systems of the brain.

The CHRNA3, CHRNB4, and CHRNA5, and several other CHRNA and CHRNB genes, have consistently been associated with severity of smoking[15]. CHRNA5 has been associated with a ‘pleasurable buzz’ from early experiences with smoking[16] and, protectively, with cocaine dependence[17]. Cocaine dependence has also been tied to CHRNA5, CHRNA3, CHRNB4[18], and CHRNB3[19]. Similarly, opioid dependence was found to correlate to polymorphisms at CHRNA3[20], CHRNA5, and CHRNB4[21]. Finally, alcohol consumption has been tied to CHRNA3[22][23], CHRNA4[24], CHRNA5, and CHRNA6[25][26], as well as to CHRNB3[27] and CHRNB4[28][29][30]. Separately, binge drinking frequency was found to correlate to polymorphisms at CHRNA4[31].

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