Signal transduction and receptor modulation

After the molecular cloning of the five subtypes of dopamine receptors, extensive work has been done aiming to determine the structural requirements for their interaction with G proteins. The approaches used involved mutagenesis, use of chimeras and synthetic peptides, as well as anti-receptor antibodies. The results ofthese studies have suggested an important role of the putative third intracellular loop for all the GPCRs in general in the interaction of the receptor with G proteins. For example, several studies using chimeric receptors have found that the third intracellular loop of a- and (-adrenergic receptors can determine the second messenger pathway to which the receptor is coupled (Kobilka etal. 1988; Strader etal. 1987). In the case of dopamine D1 and D2 receptors, peptides derived from different regions of the third intracellular loop have been used as probes for regions of the receptors that interact with G proteins (Konig et al. 1994; Voss et al. 1993; Luttrel et al. 1993; Hawes et al. 1994; Malek etal. 1993). Another approach has examined chimeras between D1 andD2 or between D2 and D3 receptors. These studies have shown that regions from the second intracellular loop of the receptor are also important for G protein interaction. For example, one group constructed a series of chimeras consisting of macaque D1 receptor containing increasing amount ofratD2S sequence (Kozell etal. 1994). Chimeras that contain the third intracellular loop of the D1 receptor stimulate cAMP formation. A chimera containing the third intracel-lular loop from D2 receptor, but the second intracellular loop from the D1 receptor has no effect on cAMP formation, whereas a chimera containing both the second intracellular loop and the third intracellular loop of D2 receptor was able to inhibit cAMP formation (Kozell et al. 1994). Other studies using D3/D2 chimeras showed that the third intracellular loop of the D2 receptor was not sufficient for the coupling to certain second messenger pathways (McAllister etal. 1993; Robinson et al. 1994, 1996). Finally, approaches using anti-receptor antibodies and site-directed mutagenesis identified some regions internal to the third intra-cellular loop of D2 receptor (Plug et al. 1992; Boundy et al. 1993), as well as residues in the transmembrane domains of the D1 (Pollok et al. 1992) and D2 (Neve et al. 1991) receptors, important for receptor interaction with G proteins. Overall the interaction of dopamine receptors with G proteins involves different domains of the receptors.

Having identified five dopamine receptor subtypes, one of the main challenges was to identify the second messenger pathways specific to each receptor. Expression of individual dopamine receptor subtypes in recombinant cell lines has enabled the characterization of the second messenger pathways to which the five receptors are coupled.

Table 15.1 Dopamine receptors

D^-like

D2-like

Di

D5

D2

D3

D4

Alternative names

Dia

Dib

Structural information (Accession no.)

h 446 aa (P21728) r 446 aa (P18901)

h 477 aa (P21918) r 475 aa (P25115)

h 443 aa (P14416)AS r 444 aa (P13953)AS m 444 aa (X55674)

h 400 aa (P35462)AS r 446 aa (P19020) m 446 aa (P30728)

h 387 aa (P21917) r 387 aa (P30729) m 387 aa (P51436)

Chromosomal location

5q35.1

4p15.1-16.1

11q22-23

3q13.3

11p15.5

Selective agonists

SKF38393, SKF81297, dihydrexine

bromocriptine, lisuride

quinelorane, PD128907, pramipexole

PD168077

Selective antagonists

SCH23390, SCH39166, SKF83566

L741626, raclopride

SB27701 1, S33084, S14297

L745870, U101958, L741742

Radioligands

[3H]-SCH23390 [125I]-SCH23982

[3H]-SCH23390 [125I]-SCH23982

[3H]-spiperone [3H]-raclopride [3H]-nemonapride

[3H]-spiperone [3H]-raclopride [3H]-nemonapride

[3H]-spiperone [3H]-nemonapride

G protein coupling

Gs/Gq

Gs/Gq

Gi/Go/Gz

Gi/Go

Gi/Go

Expression profile

striatum, nucleus accumbens, olfactory tubercle, frontal cortex hypothalamus, thalamus

hippocampus, thalamus, lateral mamillary nucleus, striatum, cerebral cortex

striatum, nucleus accumbens, olfactory tubercle, cerebral cortex

nucleus accumbens, olfactory tubercle, islands of Calleja, cerebral cortex

frontal cortex, midbrain, amygdala, hippocampus, medulla, retina

Physiological function control of motor function control of motor function, and cardiovascular function, behaviour, control of

Physiological function control of motor function control of motor function, and cardiovascular function, behaviour, control of

regulation of immediate early gene expression

prolactin and MSH secretion, cardiovascular function, regulation of immediate early gene expression

Knockout phenotype

retarded postnatal development, increased basal locomotor activity, decreased locomotor response to a novel environment, altered cognitive behaviour

increased horizontal and rearing activity, reduced anxiety, superior rotarod performance

retarded postnatal development, postural abnormalities, decreased reward response to morphine, bradykinesia, prolonged immobility disrupted pre-pulse inhibition, absence of haloperidol induced catalepsy

increased locomotor activation in a novel environment

decreased spontaneous locomotor and rearing activity, reduced novelty related exploration, superior rotarod performance

Disease relevance

Parkinson's disease, cognitivie decline, neurodegenerative disease

not clear

Parkinson's disease, schizophrenia, neurodegenerative disease, addiction

Parkinson's disease, schizophrenia, neurodegenerative disease

schizophrenia, attention deficit hyperactivity disorder

Was this article helpful?

0 0

Post a comment