Purinergisistä reseptoreista

https://journals.lww.com/nrronline/Fulltext/2023/08000/The_role_of_purinergic_receptors_in_neural_repair.9.aspx

Classification, Distribution, and Primary Roles of Purinergic Receptors in the Central Nervous System

Purinergic receptors are expressed on the cell surface and bind to and react with purines (Burnstock, 2018). Purinergic receptors fall into two major families: P1 and P2 receptors. These receptors can be activated by purines, which can also act as neurotransmitters when they bind to purinergic receptors to transmit information (Burnstock, 2008; Burnstock et al., 2012).

At present, there are several subtypes of P1 receptors: A1, A2a, A2b, and A3. These four subtypes are all G protein coupled receptors. Adenosine and AMP can activate P1 receptors (Sawynok, 2007; Ciruela, 2011). P2 receptors are divided into P2X and P2Y receptors. Seven subtypes of P2X receptors (P2X1–7) and nine subtypes of P2Y receptors (P2Y1, 2, 4, 6, 11, 12, 13, 14, and P2Y15) have been identified thus far (Abbracchio and Burnstock, 1994). ATP and ADP can both act on P2 receptors (Müller et al., 2020).

Many studies have focused on the regulatory roles of purinergic signalling in the CNS (Burnstock, 2017; Rodrigues et al., 2019). Purinergic receptor subtypes are widely distributed in the CNS and act by regulating the release of ATP and adenosine during synaptic transmission (Abbracchio et al., 2009). In the CNS, multiple purinergic receptors are expressed in glial cells, including astrocytes, microglia and oligodendrocytes. The A1 and A3 receptors inhibit promote the production of cAMP through G protein coupling while A2a and A2b receptors inhibit this process (Sciaraffia et al., 2014; Wang and Zhou, 2019).

A1 receptors can inhibit the release of glutamate, an excitatory neurotransmitter. Following CNS injury, excitatory amino acids activate N-methyl-D-aspartic acid receptors in the postsynaptic membrane, thus resulting in the release of a large amount of adenosine (Lu et al., 2003). This adenosine binds to A1 receptors in the presynaptic membrane to inhibit associated calcium channels, thus reducing the generation and release of glutamate and reducing the excitability of nerve cells to exert a protective effect (Lu and Rosenberg, 2007). In the macaque middle cerebral artery embolization model, AST-004 treatment was shown to significantly slow the growth of ischemic lesions and reduce infarct volumes; AST-004 is a novel agonist for adenosine A1 and A3 receptors. These findings suggested that the activation of adenosine A1 and A3 receptors can exert neuroprotective effects (Liston et al., 2022). A1 receptors can also reduce the accumulation of Ca²⁺ and mitochondrial Ca²⁺ overload after CNS injury to alleviate neural injury (Kashfi et al., 2017). As an important component of the P1 signalling pathway, A2 receptors are involved in regulating the pathological and physiological processes involved in CNS diseases and injuries, but with effects opposite to those of A1 receptors. The activation of A2 receptors aggravates Ca²⁺ accumulation after neural injury (Dai and Zhou, 2011).

Adenosine exerts multiple functions in the CNS, including regulating the functions of neurons and glial cells and glial signalling, and affecting neurodevelopment (McGaraughty et al., 2001). Abnormalities of adenosine and P1 receptors are involved in the changes associated with various neurodegenerative diseases such as Parkinson’s disease, Huntington’s disease and Alzheimer’s disease (Burnstock, 2008).

The P2X receptor is an ion channel receptor that binds ATP and then affects Na⁺, K⁺, and Ca²⁺ channels in the absence of a cell membrane and intracellular signal transduction (Burnstock, 2016). P2X1–7 receptors are widely expressed in astrocytes and neurons. Some of these are also expressed in oligodendrocytes, Schwann cells, and microglia. P2X receptors participate in different physiological processes in the CNS, including synaptic transmission and signal transduction between gliocytes and neurons (Lambrecht, 2000; Fu et al., 2009). Multiple subtypes of P2X receptors are expressed in CNS neurons. Of these, the P2X3 receptor is expressed in sensory neurons in the dorsal horn of the spinal cord and dorsal root ganglia (de Melo Aquino et al., 2019; Marucci et al., 2019). P2X2 and P2X4 receptors are widely expressed in the spinal cord, hippocampus, cerebral cortex and cerebellum (Khaira et al., 2009; Sivcev et al., 2020). P2X7 receptors are also expressed in axonal growth cones and presynaptic terminals. These receptors affect neuronal activity and mediate microglial and neuron-glial interactions in the pathophysiological processes involved in CNS diseases (Volonté et al., 2012; Kan et al., 2019; Miras-Portugal et al., 2021).

P2Y receptors are widely distributed in the nervous system. After being activated by extracellular purines and pyrimidine nucleotides, the P2Y receptors activate intracellular signalling pathways by coupling with G proteins (Rafehi and Müller, 2018; von Kügelgen, 2021). P2Y1, P2Y2 and P2Y12 receptors are expressed in the spinal cord, hippocampus and cerebral cortex (Puchałowicz et al., 2014; Grohmann et al., 2021). P2Y1, 2, 4, and P2Y6 receptors are expressed in the spinal cord, trigeminal ganglia and dorsal root ganglia (D’Ambrosi et al., 2006; Wen et al., 2020). P2Y2 and P2Y14 receptors are also expressed in astrocytes in the CNS (Martiáñez et al., 2012). P2Y receptors are involved in a wide range of regulatory functions, including neural signalling, glial proliferation and migration, cell differentiation, ion transport, nerve cell regeneration and nerve cell apoptosis. Extracellular ATP, released at high concentrations from intracellular stores after injury, acts on the P2Y receptors expressed in astrocytes to activate the P2Y signalling pathways which then stimulate the proliferation of astrocytes and aggravate tissue damage.

Moreover, ATP can also mediate programmed death of nerve cells through P2Y receptors. A previous study of brain injury observed an upregulation in the expression of P2Y receptors and that these high expression levels were related to the activation of glial cells in different ways. Cultured rat cortical astrocytes exhibited significant increases in the synthesis of glial fibrillary acidic protein after the administration of exogenous ATP; this might be related to the effect of ATP on P2Y receptors (Ceruti et al., 2009).

P2Y4 and P2Y12 receptors can inhibit K⁺ and Ca²⁺ channels to inhibit action potentials and affect neurotransmitter release. In the spinal cord, ATP can induce superoxide production through P2Y1 receptors (Xia and Zhu, 2014). Under pathological conditions, such as CNS injury, the expression of P2Y6 receptors on the microglia is upregulated, thus promoting the extension of microglial protrusions, enhancing phagocytosis, and inducing the production of chemokines that participate in the process of neural injury and repair (Quintas et al., 2014). The P2Y13 receptors expressed in the dorsal horn of the spinal cord and hippocampus are known to be involved in neurodevelopment and axonal growth (Guarracino et al., 2016), while P2Y1 and P2Y7 receptors act synergistically to promote the growth and extension of axons. In CNS injury, on one hand, the expression of the P2Y2 receptor increases; on the other hand, such injury leads to the massive release of extracellular ATP, which acts on P2Y2 receptors and increases intracellular Ca²⁺ concentration, thereby promoting the release of neurotransmitters and altering synaptic transmission efficiency. In addition, P2Y2 receptors may play a key role in both nerve and glial cells (Arthur et al., 2006).

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