**3. ACh receptors**

As mentioned above, the cholinergic system is involved in a wide variety of functions in peripheral as well as in CNS. ACh is the neurotransmitter widely distributed in CNS, used by motor neurons at the neuromuscular junction, and by sympathetic and parasympathetic preganglionic neurons in the autonomic nervous system (ANS), by the parasympathetic innervated organs and select sympathetic-innerved organs including sweat glands, the piloerector muscle (responsible for skin hair to stand up), and other smooth muscles such as irises, which control the diameter of the pupils. In all these, ACh effect is mediated by activating two distinct types of receptors: muscarinic acetylcholine receptors (mAChRs) and nicotinic acetylcholine receptors (nAChR) that differ in both structure and function but share common neuronal circuits. Moreover, these two receptors may co-localized in the same or in different cells, where they can interact with each other. For example, nAChRs in ganglionic cells may modulate the functions of mAChRs in target organs such as smooth muscle, cardiomyocytes, epithelium, and exocrine cells. Below, following brief descriptions of the two classes of receptors, their role in relation to the neurodegenerative diseases will be the focus.

#### **3.1 Muscarinic acetylcholine receptors (mAChRs)**

There are five subtypes of mAChRs: M1, M2, M3, M4 and M5 which are G-protein coupled receptors (GPCRs) responsive to the agonist muscarine with equal affinity [3]. Depending on the subtype of mAChR stimulated, distinct signaling pathways are activated. For example, stimulation of the M2 and M4 subtypes, leads to activation of inhibitory G-protein (Gi) which results in inhibition of cyclic AMP (cAMP) and consequent effects downstream. In contrast, activation of M1, M3 and M5 subtypes is generally coupled to a (Gq) which activates phospholipase C that leads to the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 causes mobilization of Ca2+ from intracellular stores, while DAG activates protein kinase C (PKC) isozymes [4], which can phosphorylate a multitude of downstream molecules that exert tissue-specific functions [5]. In addition, activation of mAChRs can modulate several types of ion channels and currents. For example, Ca2+ currents can be suppressed by M1 and M2 receptors in the mouse and M1 and M4 receptors in the rat, whereas M1 receptors can suppress M-type K<sup>+</sup> current in the rat [6]. Furthermore, MAP kinases and small GTPases, such as Rho and Rac proteins, are also activated by mAChRs [4]. It is worth mentioning that Gq and Gs are designation for stimulatory, whereas Gi signifies inhibitory effect on second messenger such as cAMP.

#### **3.2 Brain distribution of mAChRs**

The predominant mAChR subtypes expressed in the cortex of adult brain are: M1(40%), M2 (37%) and M4 (15%). In the hippocampus, however, 36%, 33% and *Central Nicotinic and Muscarinic Receptors in Health and Disease DOI: http://dx.doi.org/10.5772/intechopen.112447*

27% represent M1, M2 and M4, respectively. As mentioned earlier, M1 receptors are found throughout the brain with highest concentrations in cortical regions and the hippocampus. Cortical M1 receptors, most dominant in cortical layers III and V/ VI in pyramidal neurons are primarily located post-synaptically and are associated with excitatory synapses. M2 receptors, on the other hand, are highly localized in the nucleus basalis and occipital cortex, and with lesser density in the hippocampus, caudate putamen, and other cortical regions. M2 receptors are located both pre- and post-synaptically in the cortex, where the latter is present in a subset of glutamatergic synapses and GABAergic interneurons. The presynaptic M2 receptors are located on the axons of symmetric synapses and function as autoreceptors. An autoreceptor is a type of receptor located in the nerve membrane and serves as part of a negative feedback loop in signal transduction and is only sensitive to the neurotransmitters released by the neuron on which it is located. M3 receptors have similar distribution to that of M1 but with a much lower level of expression. Like M1, M3 receptors also are present in cortical pyramidal neurons and glial cells. In contrast, M4 receptors are highest in the caudate putamen and are often associated with dopaminergic neurotransmission. M5 receptors are present in very low levels in the hippocampus, substantia nigra, and ventral tegmental area.

### **3.3 Function of mAChRs**

mAChRs shape neuronal and local network processing abilities, and depending on the network involved, affect cognitive functions including learning and memory. For example, AD related-cognitive impairment is associated with reduced muscarinic cholinergic activity, although ascribing specific contribution of individual mAChR subtypes to a specific cognitive performance is not tenable due to heterogeneous distribution of mAChR subtypes within the brain [7]. Knockout studies show that mAChRs functions are subtype dependent. For instance, in paradigms requiring hippocampal processing, M1−/− animals appear to have normal learning and memory [8, 9], suggesting other AChRs may be at play. However, in paradigms thought to require interactions between the hippocampus and cortex, M1−/− animals show deficits [10]. These deficits are thought to be analogous to working memory impairment which may require communication between the two regions and possibly through recruitment of M1 receptors. Thus, mAChRs, with their potential to modulate cognition, have stimulated a high degree of interest as a therapeutic target.

#### **3.4 Nicotinic acetylcholine receptors (nAChRs)**

Advances in this area have identified various subtypes of nAChRs with distinct anatomical, physiological, and pharmacological characteristics. These ionotropic classified receptors act by directly regulating the opening of a cation channel in the neuronal membrane. It is important to note that nAChRs present at the neuromuscular junction differ from those in autonomic ganglia which are also different from those occurring in CNS, as each has its distinct subunit structure. Neuronal nicotinic receptors are primarily alph4-beta2 or homomeric alpha7 subtypes. Extensive research on these receptors has led to the suggestion of therapeutic potential for selective nicotinic receptor agonists in various neuropsychiatric and neurodegenerative disorders, including PD, AD, schizophrenia, depression, pain as well as smoking cessation [11–13].
