Nicotinic Receptors

Nicotinic acetylcholine receptors (nAChR) are ACh-gated cation channels. They are widely distributed on neurons and glial cells in the central nervous system, where they are found at postsynaptic locations of cholinergic nerve endings and also at pre-synaptic and peri-synaptic locations of many non-cholinergic neurons. Consequently nAChRs are involved in the regulation of neurotransmitter release, e.g. glutamate, GABA, dopamine, noradrenalin and serotonin. Nicotinic receptors are also expressed on glial cells.

In addition to their properties as cation channels, they are often coupled to various second messenger systems and intracellular signalling cascades, making them versatile control elements of synaptic and cellular plasticity. The Ca²⁺ permeating nAChR α7 subtype seems to be the most important for the regulation of plasticity. It has low affinity for the natural transmitters ACh and choline, and therefore is particularly capable of responding to longer lasting tonic changes in neurotransmitter.

While all nicotinic receptors are ACh-gated cation channels, the various subtypes differ in their ligand binding affinities, and in their cation selectivities, permeabilities and channel kinetics. For example, the α7 nAChR has a relatively low affinity for agonists such as nicotine, and has high Ca²⁺ permeability, and rapid channel desensitisation. The α4ß2 subtype has relatively high affinity for nicotine and preferentially flux Na⁺ and K^+, it also desensitises more slowly. The functional significance of the various subtypes and their differential distribution in the brain is not yet fully understood.

The α7 nAChR seems to play an important role in the plasticity of the central nervous system and in intracellular regulation of a variety of processes, including glucose uptake, energy metabolism and apoptosis. The link between nicotinic receptors and reduced glucose uptake has led to the suggestion that AD may be a neuro-endocrine disorder, resembling a unique form of diabetes mellitus and progressing with accompanied neuro-degeneration. Recently, nicotinic receptors have been shown to be involved in the regulation of cell survival and programmed cell death.