of the receptors for insulin and insulin-like
growth factors has also been quite well described.
Each receptor is associated with one of the
many intracellular effectors: the adenylate cyclases produce the secondary messenger cAMP; the
cGMP phosphodiesterases inactivate the messenger cGMP. Membrane-bound guanyl cyclases
function also as receptors for the atrial natriuretic
peptide (ANP) and for the peptides speract and
resact from sea urchin eggs. The murine guanylate cyclase/ANP receptor is a polypeptide with a
hormone-binding extracellular domain of 469
amino acids, a membrane segment of 21 amino
acids, and an enzymically active intracellular
domain of 567 amino acids [164]. The intracellular domains of the receptors for insulin, insulinlike and other growth factors have tyrosine kinase
activity. Phbspolipase C acts on phosphatidyl-4,Sbisphosphate to release both diacylglycerol,
which activates protein kinase C, and inositol1,4,S-trisphosphate (ins-1,4,S-P3)' which elevates
the cytoplasmic concentration of the secondary
messenger Ca 2 + by mobilizing intracellular reserves and by opening ion channels. The ins-1,4,S-P3
receptors of the mouse and rat function as calcium channels. They are polypeptides of about
2750 amino acids with seven or eight transmembrane segments close to the C-terminus; these
exist as several tissue-specific variants. The corresponding receptor from Drosophila melanogaster
agrees in 58 % of its amino acids with that of the
mammals [139, 152]. Ins-1,4,S-P3 is either
dephosphorylated to ins-1,4-P2 and recycled during lipid synthesis, or further phosphorylated to
ins-P4, ins-P5 and ins-P6, which are all apparently
involved in the regulation of the Ca2+ concentration [218].
8.9.1 G-Protein-Linked Receptors
To date, more than 100 G-protein-linked receptor
types and SUbtypes are known; they show
between 20 and more than 90 % sequence agreement and make up their own super-family. The
similarity is more marked between receptors
binding the same ligands [5, 17,211]. This receptor family includes the a- and ~-adrenergic receptors (aI, a2, ~1, ~2, ~3), the muscariniccholinergic receptors (m1-mS), the receptors for
histamine, serotonin, tyramine and dopamine
[69, 190,247], the receptors for substance P, VIP
and endothelin [78, 121, 207], and the receptors
for the glycoproteins of the adenohypophysis LH,
FSH, TSH and CG [189]. The visual-pigment
8.9.1 G-Protein-Linked Receptors
309
(opsins) and olfactory receptors of vertebrates
and insects are significantly homologous to the Gprotein-linked hormone receptors [26, 49]. It
appears in this case that one signal transduction
system has been adapted to cover many signals in
the course of evolution. The visual pigments and
corresponding G-proteins (transducins) will be
examined in more detail in Chapter 19. All the Gprotein-linked receptors consist of a polypeptide
chain of 402-590 amino acids. The genes of the
opsins and various hormone receptors differ in
the number of their introns. In contrast, the genes
for ~2-adrenergic receptors of the hamster and of
man have no introns, but flanking repetitive
sequences are present. Thus, we are probably
dealing here with functional copies of a processed
mRNA. The N-terminal domains of the receptors
always carry sites for N-linked glycosylation, and
the C-terminal domains have several sites which
are phosphorylated by specific protein kinases
[10]; phosphorylation reduces sensitivity in the
case of the ~-adrenergic receptor. The membrane
topology corresponds to that of bacterial rhodopsin with seven transmembrane domains (Fig 8.7),
the amino acid sequences of which are highly conserved. The serotonin receptor of Drosophila
melanogaster is unique in having eight transmembrane domains [235]. The second and third transmembrane domains of the adrenergic and
muscarinic-cholinergic receptors contain acidic
amino acid residues which probably form the
binding site for the basic ligands. The intracellular
region interacts with the G-proteins, which in
turn affect the associated effectors. The three ~adrenergic receptors, the serotoninergic receptor
SHT-1A and the dopaminergic receptor D1
stimulate membrane-bound adenylate cyclase via
a Gs-protein, whilst the a2-adrenergic receptors,
the muscarinic-cholinergic receptors m2 and m4
and the dopaminergic receptor D2 inhibit this
effector enzyme via a G1-protein. The a1adrenergic receptors, the muscarinic-cholinergic
receptors m1, m3 and mS, and the serotoninergic
receptor SHT-2 regulate the hydrolysis of phosphoinositollipids by phospholipases A2 or C via a
Gj- or Go-protein, and thereby modulate the production of the second messengers DAG (diacylglycerol) and ins-1,4,S-P3; they may also regulate
other effectors such as K+ channels [211].
The G-proteins function in a cyclic fashion.
The non-activated protein is a complex of three
polypeptides, a-y, with a GDP bound to the
a chain. Activation of the protein results in the
exchange of GDP for GTP and the separation of
the a chain from the Wy dimer. The free GTP-
growth factors has also been quite well described.
Each receptor is associated with one of the
many intracellular effectors: the adenylate cyclases produce the secondary messenger cAMP; the
cGMP phosphodiesterases inactivate the messenger cGMP. Membrane-bound guanyl cyclases
function also as receptors for the atrial natriuretic
peptide (ANP) and for the peptides speract and
resact from sea urchin eggs. The murine guanylate cyclase/ANP receptor is a polypeptide with a
hormone-binding extracellular domain of 469
amino acids, a membrane segment of 21 amino
acids, and an enzymically active intracellular
domain of 567 amino acids [164]. The intracellular domains of the receptors for insulin, insulinlike and other growth factors have tyrosine kinase
activity. Phbspolipase C acts on phosphatidyl-4,Sbisphosphate to release both diacylglycerol,
which activates protein kinase C, and inositol1,4,S-trisphosphate (ins-1,4,S-P3)' which elevates
the cytoplasmic concentration of the secondary
messenger Ca 2 + by mobilizing intracellular reserves and by opening ion channels. The ins-1,4,S-P3
receptors of the mouse and rat function as calcium channels. They are polypeptides of about
2750 amino acids with seven or eight transmembrane segments close to the C-terminus; these
exist as several tissue-specific variants. The corresponding receptor from Drosophila melanogaster
agrees in 58 % of its amino acids with that of the
mammals [139, 152]. Ins-1,4,S-P3 is either
dephosphorylated to ins-1,4-P2 and recycled during lipid synthesis, or further phosphorylated to
ins-P4, ins-P5 and ins-P6, which are all apparently
involved in the regulation of the Ca2+ concentration [218].
8.9.1 G-Protein-Linked Receptors
To date, more than 100 G-protein-linked receptor
types and SUbtypes are known; they show
between 20 and more than 90 % sequence agreement and make up their own super-family. The
similarity is more marked between receptors
binding the same ligands [5, 17,211]. This receptor family includes the a- and ~-adrenergic receptors (aI, a2, ~1, ~2, ~3), the muscariniccholinergic receptors (m1-mS), the receptors for
histamine, serotonin, tyramine and dopamine
[69, 190,247], the receptors for substance P, VIP
and endothelin [78, 121, 207], and the receptors
for the glycoproteins of the adenohypophysis LH,
FSH, TSH and CG [189]. The visual-pigment
8.9.1 G-Protein-Linked Receptors
309
(opsins) and olfactory receptors of vertebrates
and insects are significantly homologous to the Gprotein-linked hormone receptors [26, 49]. It
appears in this case that one signal transduction
system has been adapted to cover many signals in
the course of evolution. The visual pigments and
corresponding G-proteins (transducins) will be
examined in more detail in Chapter 19. All the Gprotein-linked receptors consist of a polypeptide
chain of 402-590 amino acids. The genes of the
opsins and various hormone receptors differ in
the number of their introns. In contrast, the genes
for ~2-adrenergic receptors of the hamster and of
man have no introns, but flanking repetitive
sequences are present. Thus, we are probably
dealing here with functional copies of a processed
mRNA. The N-terminal domains of the receptors
always carry sites for N-linked glycosylation, and
the C-terminal domains have several sites which
are phosphorylated by specific protein kinases
[10]; phosphorylation reduces sensitivity in the
case of the ~-adrenergic receptor. The membrane
topology corresponds to that of bacterial rhodopsin with seven transmembrane domains (Fig 8.7),
the amino acid sequences of which are highly conserved. The serotonin receptor of Drosophila
melanogaster is unique in having eight transmembrane domains [235]. The second and third transmembrane domains of the adrenergic and
muscarinic-cholinergic receptors contain acidic
amino acid residues which probably form the
binding site for the basic ligands. The intracellular
region interacts with the G-proteins, which in
turn affect the associated effectors. The three ~adrenergic receptors, the serotoninergic receptor
SHT-1A and the dopaminergic receptor D1
stimulate membrane-bound adenylate cyclase via
a Gs-protein, whilst the a2-adrenergic receptors,
the muscarinic-cholinergic receptors m2 and m4
and the dopaminergic receptor D2 inhibit this
effector enzyme via a G1-protein. The a1adrenergic receptors, the muscarinic-cholinergic
receptors m1, m3 and mS, and the serotoninergic
receptor SHT-2 regulate the hydrolysis of phosphoinositollipids by phospholipases A2 or C via a
Gj- or Go-protein, and thereby modulate the production of the second messengers DAG (diacylglycerol) and ins-1,4,S-P3; they may also regulate
other effectors such as K+ channels [211].
The G-proteins function in a cyclic fashion.
The non-activated protein is a complex of three
polypeptides, a-y, with a GDP bound to the
a chain. Activation of the protein results in the
exchange of GDP for GTP and the separation of
the a chain from the Wy dimer. The free GTP-