manu/mldr-zoomed-100char-total-queries-documents

chunk_id stringlengths 3 9	chunk stringlengths 1 100
72_32	Four G protein gated inwardly-rectifying potassium (GIRK) channel subunits have been identified in
72_33	mammals: GIRK1, GIRK2, GIRK3, and GIRK4. The GIRK subunits come together to form GIRK ion channels.
72_34	These ion channels, once activated, allow for the flow of potassium ions (K+) from the
72_35	extracellular space surrounding the cell across the plasma membrane and into the cytoplasm. Each
72_36	channel consists of domains which span the plasma membrane, forming the K+-selective pore region
72_37	through which the K+ ions will flow. Both the N-and C-terminal ends of the GIRK channels are
72_38	located within the cytoplasm. These domains interact directly with the βγ-complex of the G protein,
72_39	leading to activation of the K+ channel. . These domains on the N-and C-terminal ends which
72_40	interact with the G proteins contain certain residues which are critical for the proper activation
72_41	of the GIRK channel. In GIRK4, the N-terminal residue is His-64 and the C-terminal residue is
72_42	Leu-268; in GIRK1 they are His-57 and Leu-262, respectively. Mutations in these domains lead to the
72_43	channel's desensitivity to the βγ-complex and therefore reduce the activation of the GIRK channel.
72_44	The four GIRK subunits are 80-90% similar in their pore-forming and transmembrane domains, a
72_45	feature accountable by the similarities in their structures and sequences. GIRK2, GIRK3, and GIRK4
72_46	share an overall identity of 62% with each other, while GIRK1 only shares 44% identity with the
72_47	others. Because of their similarity, the GIRK channel subunits can come together easily to form
72_48	heteromultimers (a protein with two or more different polypeptide chains). GIRK1, GIRK2, and GIRK3
72_49	show abundant and overlapping distribution in the central nervous system (CNS) while GIRK1 and
72_50	GIRK4 are found primarily in the heart. GIRK1 combines with GIRK2 in the CNS and GIRK4 in the
72_51	atrium to form heterotetramers; each final heterotetramer contains two GIRK1 subunits and two GIRK2
72_52	or GIRK4 subunits. GIRK2 subunits can also form homotetramers in the brain, while GIRK4 subunits
72_53	can form homotetramers in the heart. GIRK1 subunits have not been shown to be able to form
72_54	functional homotetramers. Though GIRK3 subunits are found in the CNS, their role in forming
72_55	functional ion channels is still unknown.
72_56	Subtypes and respective functions GIRKs found in the heart
72_57	One G protein-gated potassium channel is the inward-rectifing potassium channel (IKACh) found in
72_58	cardiac muscle (specifically, the sinoatrial node and atria), which contributes to the regulation
72_59	of heart rate. These channels are almost entirely dependent on G protein activation, making them
72_60	unique when compared to other G protein-gated channels. Activation of the IKACh channels begins
72_61	with release of acetylcholine (ACh) from the vagus nerve onto pacemaker cells in the heart. ACh
72_62	binds to the M2 muscarinic acetylcholine receptors, which interact with G proteins and promote the
72_63	dissociation of the Gα subunit and Gβγ-complex. IKACh is composed of two homologous GIRK channel
72_64	subunits: GIRK1 and GIRK4. The Gβγ-complex binds directly and specifically to the IKACh channel
72_65	through interactions with both the GIRK1 and GIRK4 subunits. Once the ion channel is activated, K+
72_66	ions flow out of the cell and cause it to hyperpolarize. In its hyperpolarized state, the neuron
72_67	cannot fire action potentials as quickly, which slows the heartbeat.
72_68	GIRKs found in the brain
72_69	The G protein inward rectifying K+ channel found in the CNS is a heterotetramer composed of GIRK1
72_70	and GIRK2 subunits and is responsible for maintaining the resting membrane potential and
72_71	excitability of the neuron. Studies have shown the largest concentrations of the GIRK1 and GIRK2
72_72	subunits to be in the dendritic areas of neurons in the CNS. These areas, which are both
72_73	extrasynaptic (exterior to a synapse) and perisynaptic (near a synapse), correlate with the large
72_74	concentration of GABAB receptors in the same areas. Once the GABAB receptors are activated by
72_75	their ligands, they allow for the dissociation of the G protein into its individual α-subunit and
72_76	βγ-complex so it can in turn activate the K+ channels. The G proteins couple the inward rectifying
72_77	K+ channels to the GABAB receptors, mediating a significant part of the GABA postsynaptic
72_78	inhibition.
72_79	Furthermore, GIRKs have been found to play a role in a group of serotonergic neurons in the dorsal
72_80	raphe nucleus, specifically those associated with the neuropeptide hormone orexin. The 5-HT1A
72_81	receptor, a serotonin receptor and type of GPCR, has been shown to be coupled directly with the
72_82	α-subunit of a G protein, while the βγ-complex activates GIRK without use of a second messenger.
72_83	The subsequent activation of the GIRK channel mediates hyperpolarization of orexin neurons, which
72_84	regulate the release of many other neurotransmitters including noradrenaline and acetylcholine.
72_85	Calcium channels Structure
72_86	In addition to the subset of potassium channels that are directly gated by G proteins, G proteins
72_87	can also directly gate certain calcium ion channels in neuronal cell membranes. Although membrane
72_88	ion channels and protein phosphorylation are typically indirectly affected by G protein-coupled
72_89	receptors via effector proteins (such as phospholipase C and adenylyl cyclase) and second
72_90	messengers (such as inositol triphosphate, diacylglycerol and cyclic AMP), G proteins can short
72_91	circuit the second-messenger pathway and gate the ion channels directly. Such bypassing of the
72_92	second-messenger pathways is observed in mammalian cardiac myocytes and associated sarcolemmal
72_93	vesicles in which Ca2+ channels are able to survive and function in the absence of cAMP, ATP or
72_94	protein kinase C when in the presence of the activated α-subunit of the G protein. For example, Gα,
72_95	which is stimulatory to adenylyl cyclase, acts on the Ca2+ channel directly as an effector. This
72_96	short circuit is membrane-delimiting, allowing direct gating of calcium channels by G proteins to
72_97	produce effects more quickly than the cAMP cascade could. This direct gating has also been found in
72_98	specific Ca2+ channels in the heart and skeletal muscle T tubules.
72_99	Function
72_100	Several high-threshold, slowly inactivating calcium channels in neurons are regulated by G
72_101	proteins. The activation of α-subunits of G proteins has been shown to cause rapid closing of
72_102	voltage-dependent Ca2+ channels, which causes difficulties in the firing of action potentials. This
72_103	inhibition of voltage-gated Calcium channels by G protein-coupled receptors has been demonstrated
72_104	in the dorsal root ganglion of a chick among other cell lines. Further studies have indicated roles
72_105	for both Gα and Gβγ subunits in the inhibition of Ca2+ channels. The research geared to defining
72_106	the involvement of each subunit, however, has not uncovered the specificity or mechanisms by which
72_107	Ca2+ channels are regulated.
72_108	The acid-sensing ion channel ASIC1a is a specific G protein-gated Ca2+ channel. The upstream M1
72_109	muscarinic acetylcholine receptor binds to Gq-class G proteins. Blocking this channel with the
72_110	agonist oxotremorine methiodide was shown to inhibit ASIC1a currents. ASIC1a currents have also
72_111	been shown to be inhibited in the presence of oxidizing agents and potentiated in the presence of
72_112	reducing agents. A decrease and increase in acid-induced intracellular Ca2+ accumulation were
72_113	found, respectively.
72_114	Sodium channels
72_115	Patch clamp measurements suggest a direct role for Gα in the inhibition of fast Na+ current within
72_116	cardiac cells. Other studies have found evidence for a second-messenger pathway which may
72_117	indirectly control these channels. Whether G proteins indirectly or directly activate Na+ ion
72_118	channels not been defined with complete certainty.
72_119	Chloride channels
72_120	Chloride channel activity in epithelial and cardiac cells has been found to be G protein-dependent.
72_121	However, the cardiac channel that has been shown to be directly gated by the Gα subunit has not
72_122	yet been identified. As with Na+ channel inhibition, second-messenger pathways cannot be discounted
72_123	in Cl− channel activation.
72_124	Studies done on specific Cl− channels show differing roles of G protein activation. It has been
72_125	shown that G proteins directly activate one type of Cl− channel in skeletal muscle. Other studies,
72_126	in CHO cells, have demonstrated a large conductance Cl− channel to be activated differentially by
72_127	CTX- and PTX-sensitive G proteins. The role of G proteins in the activation of Cl− channels is a
72_128	complex area of research that is ongoing.
72_129	Clinical significance and ongoing research
72_130	Mutations in G proteins associated with G protein-gated ion channels have been shown to be involved
72_131	in diseases such as epilepsy, muscular diseases, neurological diseases, and chronic pain, among

72_32

Four G protein gated inwardly-rectifying potassium (GIRK) channel subunits have been identified in

72_33

mammals: GIRK1, GIRK2, GIRK3, and GIRK4. The GIRK subunits come together to form GIRK ion channels.

72_34

These ion channels, once activated, allow for the flow of potassium ions (K+) from the

72_35

extracellular space surrounding the cell across the plasma membrane and into the cytoplasm. Each

72_36

channel consists of domains which span the plasma membrane, forming the K+-selective pore region

72_37

through which the K+ ions will flow. Both the N-and C-terminal ends of the GIRK channels are

72_38

located within the cytoplasm. These domains interact directly with the βγ-complex of the G protein,

72_39

leading to activation of the K+ channel. . These domains on the N-and C-terminal ends which

72_40

interact with the G proteins contain certain residues which are critical for the proper activation

72_41

of the GIRK channel. In GIRK4, the N-terminal residue is His-64 and the C-terminal residue is

72_42

Leu-268; in GIRK1 they are His-57 and Leu-262, respectively. Mutations in these domains lead to the

72_43

channel's desensitivity to the βγ-complex and therefore reduce the activation of the GIRK channel.

72_44

The four GIRK subunits are 80-90% similar in their pore-forming and transmembrane domains, a

72_45

feature accountable by the similarities in their structures and sequences. GIRK2, GIRK3, and GIRK4

72_46

share an overall identity of 62% with each other, while GIRK1 only shares 44% identity with the

72_47

others. Because of their similarity, the GIRK channel subunits can come together easily to form

72_48

heteromultimers (a protein with two or more different polypeptide chains). GIRK1, GIRK2, and GIRK3

72_49

show abundant and overlapping distribution in the central nervous system (CNS) while GIRK1 and

72_50

GIRK4 are found primarily in the heart. GIRK1 combines with GIRK2 in the CNS and GIRK4 in the

72_51

atrium to form heterotetramers; each final heterotetramer contains two GIRK1 subunits and two GIRK2

72_52

or GIRK4 subunits. GIRK2 subunits can also form homotetramers in the brain, while GIRK4 subunits

72_53

can form homotetramers in the heart. GIRK1 subunits have not been shown to be able to form

72_54

functional homotetramers. Though GIRK3 subunits are found in the CNS, their role in forming

72_55

functional ion channels is still unknown.

72_56

Subtypes and respective functions GIRKs found in the heart

72_57

One G protein-gated potassium channel is the inward-rectifing potassium channel (IKACh) found in

72_58

cardiac muscle (specifically, the sinoatrial node and atria), which contributes to the regulation

72_59

of heart rate. These channels are almost entirely dependent on G protein activation, making them

72_60

unique when compared to other G protein-gated channels. Activation of the IKACh channels begins

72_61

with release of acetylcholine (ACh) from the vagus nerve onto pacemaker cells in the heart. ACh

72_62

binds to the M2 muscarinic acetylcholine receptors, which interact with G proteins and promote the

72_63

dissociation of the Gα subunit and Gβγ-complex. IKACh is composed of two homologous GIRK channel

72_64

subunits: GIRK1 and GIRK4. The Gβγ-complex binds directly and specifically to the IKACh channel

72_65

through interactions with both the GIRK1 and GIRK4 subunits. Once the ion channel is activated, K+

72_66

ions flow out of the cell and cause it to hyperpolarize. In its hyperpolarized state, the neuron

72_67

cannot fire action potentials as quickly, which slows the heartbeat.

72_68

GIRKs found in the brain

72_69

The G protein inward rectifying K+ channel found in the CNS is a heterotetramer composed of GIRK1

72_70

and GIRK2 subunits and is responsible for maintaining the resting membrane potential and

72_71

excitability of the neuron. Studies have shown the largest concentrations of the GIRK1 and GIRK2

72_72

subunits to be in the dendritic areas of neurons in the CNS. These areas, which are both

72_73

extrasynaptic (exterior to a synapse) and perisynaptic (near a synapse), correlate with the large

72_74

concentration of GABAB receptors in the same areas. Once the GABAB receptors are activated by

72_75

their ligands, they allow for the dissociation of the G protein into its individual α-subunit and

72_76

βγ-complex so it can in turn activate the K+ channels. The G proteins couple the inward rectifying

72_77

K+ channels to the GABAB receptors, mediating a significant part of the GABA postsynaptic

72_78

inhibition.

72_79

Furthermore, GIRKs have been found to play a role in a group of serotonergic neurons in the dorsal

72_80

raphe nucleus, specifically those associated with the neuropeptide hormone orexin. The 5-HT1A

72_81

receptor, a serotonin receptor and type of GPCR, has been shown to be coupled directly with the

72_82

α-subunit of a G protein, while the βγ-complex activates GIRK without use of a second messenger.

72_83

The subsequent activation of the GIRK channel mediates hyperpolarization of orexin neurons, which

72_84

regulate the release of many other neurotransmitters including noradrenaline and acetylcholine.

72_85

Calcium channels Structure

72_86

In addition to the subset of potassium channels that are directly gated by G proteins, G proteins

72_87

can also directly gate certain calcium ion channels in neuronal cell membranes. Although membrane

72_88

ion channels and protein phosphorylation are typically indirectly affected by G protein-coupled

72_89

receptors via effector proteins (such as phospholipase C and adenylyl cyclase) and second

72_90

messengers (such as inositol triphosphate, diacylglycerol and cyclic AMP), G proteins can short

72_91

circuit the second-messenger pathway and gate the ion channels directly. Such bypassing of the

72_92

second-messenger pathways is observed in mammalian cardiac myocytes and associated sarcolemmal

72_93

vesicles in which Ca2+ channels are able to survive and function in the absence of cAMP, ATP or

72_94

protein kinase C when in the presence of the activated α-subunit of the G protein. For example, Gα,

72_95

which is stimulatory to adenylyl cyclase, acts on the Ca2+ channel directly as an effector. This

72_96

short circuit is membrane-delimiting, allowing direct gating of calcium channels by G proteins to

72_97

produce effects more quickly than the cAMP cascade could. This direct gating has also been found in

72_98

specific Ca2+ channels in the heart and skeletal muscle T tubules.

72_99

Function

72_100

Several high-threshold, slowly inactivating calcium channels in neurons are regulated by G

72_101

proteins. The activation of α-subunits of G proteins has been shown to cause rapid closing of

72_102

voltage-dependent Ca2+ channels, which causes difficulties in the firing of action potentials. This

72_103

inhibition of voltage-gated Calcium channels by G protein-coupled receptors has been demonstrated

72_104

in the dorsal root ganglion of a chick among other cell lines. Further studies have indicated roles

72_105

for both Gα and Gβγ subunits in the inhibition of Ca2+ channels. The research geared to defining

72_106

the involvement of each subunit, however, has not uncovered the specificity or mechanisms by which

72_107

Ca2+ channels are regulated.

72_108

The acid-sensing ion channel ASIC1a is a specific G protein-gated Ca2+ channel. The upstream M1

72_109

muscarinic acetylcholine receptor binds to Gq-class G proteins. Blocking this channel with the

72_110

agonist oxotremorine methiodide was shown to inhibit ASIC1a currents. ASIC1a currents have also

72_111

been shown to be inhibited in the presence of oxidizing agents and potentiated in the presence of

72_112

reducing agents. A decrease and increase in acid-induced intracellular Ca2+ accumulation were

72_113

found, respectively.

72_114

Sodium channels

72_115

Patch clamp measurements suggest a direct role for Gα in the inhibition of fast Na+ current within

72_116

cardiac cells. Other studies have found evidence for a second-messenger pathway which may

72_117

indirectly control these channels. Whether G proteins indirectly or directly activate Na+ ion

72_118

channels not been defined with complete certainty.

72_119

Chloride channels

72_120

Chloride channel activity in epithelial and cardiac cells has been found to be G protein-dependent.

72_121

However, the cardiac channel that has been shown to be directly gated by the Gα subunit has not

72_122

yet been identified. As with Na+ channel inhibition, second-messenger pathways cannot be discounted

72_123

in Cl− channel activation.

72_124

Studies done on specific Cl− channels show differing roles of G protein activation. It has been

72_125

shown that G proteins directly activate one type of Cl− channel in skeletal muscle. Other studies,

72_126

in CHO cells, have demonstrated a large conductance Cl− channel to be activated differentially by

72_127

CTX- and PTX-sensitive G proteins. The role of G proteins in the activation of Cl− channels is a

72_128

complex area of research that is ongoing.

72_129

Clinical significance and ongoing research

72_130

Mutations in G proteins associated with G protein-gated ion channels have been shown to be involved

72_131

in diseases such as epilepsy, muscular diseases, neurological diseases, and chronic pain, among