The role of the neuromodulator adenosine in alcohol's actions

Abstract

The interaction between the neuromodulator adenosine and adenosine receptors on the surface of neurons modifies the neurons' responses to neurotransmitters. The activated adenosine receptors alter the levels of small signaling molecules (i.e., second messengers) in the cells. Depending on the receptors and cells involved, these changes can make it easier or more difficult for neurotransmitters to excite the cell. Adenosine's activity is regulated by proteins called nucleoside transporters, which carry adenosine into and out of the cell. Alcohol interferes with the function of the adenosine system. For example, both acute and chronic alcohol exposure affect the function of the adenosine-carrying nucleoside transporters, thereby indirectly altering the second-messenger levels in the cells. Through this mechanism, adenosine may mediate some of alcohol's effects, such as intoxication, motor incoordination, and sedation.

Figure 1

The adenosine A₁ and A₂ receptors affect cell function by modulating the activities of the enzymes adenylyl cyclase and phospholipase C. Through their association with inhibitory and stimulatory G proteins, A₁ inhibits and A₂ activates adenylyl cyclase, the enzyme that produces the second messenger cAMP. In turn, cAMP activates the enzyme protein kinase A (PKA), which adds phosphate groups to (i.e., phosphorylates) various proteins. For example, PKA phosphorylates protein channels, which allow the transport of ions across the cell membrane, and transcription factors, which alter gene activity. Phosphorylation modifies the activities of these proteins. A₁ also activates phospholipase C, which produces the second messenger diacylglycerol. This substance activates the enzyme protein kinase C, which also phosphorylates certain proteins.

Figure 2

The effects of acute alcohol exposure on cAMP production and extracellular adenosine accumulation. (A) In NG108-15 cells exposed to alcohol for 10 minutes, the cAMP production increased by about 50 percent compared with untreated control cells. Addition of the enzyme adenosine deaminase (ADA), which breaks down adenosine, or of the adenosine receptor antagonist IBMX prevented the alcohol-induced increase in cAMP production. (B) When S49 cells were treated with alcohol for 10 minutes, the adenosine concentration in the growth medium almost doubled compared with untreated control cells.

Figure 3

A model of the association between the phosphorylation state of the adenosine-carrying nucleoside transporter and its sensitivity to acute alcohol effects. The enzyme protein kinase A (PKA) is thought to add phosphate groups to (i.e., phosphorylate) the nucleoside transporter. Only the phosphorylated transporter is sensitive to acute alcohol exposure. If the phosphate groups are missing (i.e., the transporter is dephosphorylated), the transporter becomes insensitive to acute alcohol exposure.

Figure 4

Protein kinase A (PKA) and protein kinase C (PKC) have opposing effects on the adenosine transporter’s (T’s) sensitivity to alcohol. (A) In cells that have been exposed to alcohol, PKA is thought to add phosphate groups (P) to the transporter that render it sensitive to a first-time exposure to alcohol (i.e., adenosine is not transported into the cell). (B) Conversely, after chronic alcohol exposure, PKC activates an enzyme called protein phosphatase, which removes phosphate groups from proteins, thereby rendering the transporter tolerant to alcohol’s effects (i.e., adenosine is transported into the cell even after an acute alcohol dose). This phenomenon represents an aspect of tolerance, namely, the reduced responsiveness to a previously effective drug.