Những thay đổi cấu trúc và chức năng ở hồi hải mã do suy giáp

Metabolic Brain Disease - Tập 25 - Trang 339-354 - 2010
Christos Koromilas1, Charis Liapi1, Kleopatra H. Schulpis2, Konstantinos Kalafatakis1, Apostolos Zarros1,3, Stylianos Tsakiris3
1Department of Pharmacology, Medical School, National & Kapodistrian University of Athens, Athens, Greece
2Institute of Child Health, Aghia Sophia Children’s Hospital, Athens, Greece
3Department of Physiology, Medical School, National & Kapodistrian University of Athens, Athens, Greece

Tóm tắt

Hormone tuyến giáp (THs) có tác động rộng rãi đến hệ thần kinh trung ương (CNS). Suy giáp, đặc biệt trong quá trình phát triển của CNS, có thể dẫn đến những thay đổi về cấu trúc và chức năng (chủ yếu gây ra tình trạng chậm phát triển tâm thần). Hồi hải mã được coi là một trong những cấu trúc quan trọng nhất của CNS, trong khi việc điều tra và hiểu biết về những tương tác trực tiếp và gián tiếp của nó với các hormone tuyến giáp có thể cung cấp thông tin quan trọng về cơ sở thần kinh sinh học của tình trạng chậm phát triển tâm thần do suy giáp (thường gặp trong thực hành lâm sàng) và rối loạn chức năng thần kinh - hành vi. Thiếu hụt hormone tuyến giáp trong giai đoạn thai nhi và/hoặc sơ sinh tạo ra những tác động có hại đối với sự tăng trưởng và phát triển thần kinh (như giảm kết nối synapse, chậm myelin hóa, rối loạn di chuyển neuron, lệch hướng các projesct axon, giảm tạo synapse và thay đổi nồng độ của các chất dẫn truyền thần kinh). Mặt khác, rối loạn tuyến giáp khởi phát ở người lớn thường liên quan đến những bất thường về thần kinh và hành vi. Trong cả hai trường hợp, có vẻ như xảy ra những thay đổi về gen và protein. Mục tiêu của bài tổng quan này là cung cấp một cái nhìn tổng quát cập nhật về kiến thức hiện có liên quan đến những thay đổi đã đề cập xảy ra ở hồi hải mã do suy giáp khởi phát ở thai nhi, sơ sinh hoặc người lớn.

Từ khóa

#suy giáp #hormone tuyến giáp #hồi hải mã #phát triển thần kinh #rối loạn chức năng thần kinh-hành vi #bất thường thần kinh

Tài liệu tham khảo

Altman J, Das GD (1966) Autoradiographic and histological studies of postnatal neurogenesis. I. A longitudinal investigation of the kinetics, migration and transformation of cells incorporating tritiated thymidine in neonate rats, with special reference to postnatal neurogenesis in some brain regions. J Comp Neurol 126:337–389 Altman J, Bayer SA (1990a) Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. J Comp Neurol 301:365–381 Altman J, Bayer SA (1990b) Prolonged sojourn of developing pyramidal cells in the intermediate zone of the hippocampus and their settling in the stratum pyramidale. J Comp Neurol 301:343–364 Alvarez-Dolado M, Iglesias T, Rodríguez-Peña A, Bernal J, Muñoz A (1994) Expression of neurotrophins and the trk family of neurotrophin receptors in normal and hypothyroid rat brain. Brain Res Mol Brain Res 27:249–257 Alvarez-Dolado M, González-Sancho JM, Bernal J, Muñoz A (1998) Developmental expression of the tenascin-C is altered by hypothyroidism in the rat brain. Neuroscience 84:309–322 Alvarez-Dolado M, Ruiz M, Del Río JA, Alcántara S, Burgaya F, Sheldon M, Nakajima K, Bernal J, Howell BW, Curran T, Soriano E, Muñoz A (1999) Thyroid hormone regulates reelin and dab1 expression during brain development. J Neurosci 19:6979–6993 Alvarez-Dolado M, Figueroa A, Kozlov S, Sonderegger P, Furley AJ, Muñoz A (2001) Thyroid hormone regulates TAG-1 expression in the developing rat brain. Eur J Neurosci 14:1209–1218 Alva-Sánchez C, Ortiz-Butrón R, Cuéllar-García M, Hernández-García A, Pacheco-Rosado J (2002) Anatomical changes in CA3 hippocampal region by hypothyroidism in rats. Proc West Pharmacol Soc 45:125–126 Alva-Sánchez C, Medina-Canales MG, Ramos-Godínez MP, Sánchez-Espíndola ME, Becerril-Montes A (2007) Ultrastructural morphology of hypothyroid hippocampal pyramidal cells reveals apoptotic neuronal death. Acta Microscopica 16:325–326 Alva-Sánchez C, Becerril A, Anguiano B, Aceves C, Pacheco-Rosado J (2009) Participation of NMDA-glutamatergic receptors in hippocampal neuronal damage caused by adult-onset hypothyroidism. Neurosci Lett 453:178–181 Alzoubi KH, Gerges NZ, Alkadhi KA (2005) Levothyroxin restores hypothyroidism-induced impairment of LTP of hippocampal CA1: electrophysiological and molecular studies. Exp Neurol 195:330–341 Amaral DG, Dent JA (1981) Development of the mossy fibers of the dentate gyrus: I. A light and electron microscopic study of the mossy fibers and their expansions. J Comp Neurol 195:51–86 Ambrogini P, Cuppini R, Ferri P, Mancini C, Ciaroni S, Voci A, Gerdoni E, Gallo G (2005) Thyroid hormones affect neurogenesis in the dentate gyrus of adult rat. Neuroendocrinology 81:244–253 Appleyard ME (1995) Acetylcholinesterase induces long-term potentiation in CA1 pyramidal cells by a mechanism dependent on metabotropic glutamate receptors. Neurosci Lett 190:25–28 Ausó E, Lavado-Autric R, Cuevas E, Del Rey FE, Morreale De Escobar G, Berbel P (2004) A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology 145:4037–4047 Bartus RT, Dean RL 3rd, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414 Battastini AM, da Rocha JB, Barcellos CK, Dias RD, Sarkis JJ (1991) Characterization of an ATP diphosphohydrolase (EC 3.6.1.5) in synaptosomes from cerebral cortex of adult rats. Neurochem Res 16:1303–1310 Battie CA, Verity MA (1979) Membrane enzyme development in nerve ending mitochondria during neonatal hypothyroidism. Dev Neurosci 2:139–148 Baudier J, Deloulme JC, Van Dorsselaer A, Black D, Matthes HW (1991) Purification and characterization of a brain-specific protein kinase C substrate, neurogranin (p17). Identification of a consensus amino acid sequence between neurogranin and neuromodulin (GAP43) that corresponds to the protein kinase C phosphorylation site and the calmodulin-binding domain. J Biol Chem 266:229–237 Bayer SA (1980) Development of the hippocampal region in the rat. I. Neurogenesis examined with 3H-thymidine autoradiography. J Comp Neurol 190:87–114 Berbel P, Marco P, Cerezo JR, DeFelipe J (1996) Distribution of parvalbumin immunoreactivity in the neocortex of hypothyroid adult rats. Neurosci Lett 204:65–68 Bernal J (2005) Thyroid hormones and brain development. Vitam Horm 71:95–122 Bernal J (2007) Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 3:249–259 Braganhol E, Bruno AN, Bavaresco L, Barreto-Chaves ML, Sarkis JJ, Battastini AM (2006) Neonatal hypothyroidism affects the adenine nucleotides metabolism in astrocyte cultures from rat brain. Neurochem Res 31:449–454 Broude E, McAtee M, Kelley MS, Bregman BS (1997) c-Jun expression in adult rat dorsal root ganglion neurons: differential response after central or peripheral axotomy. Exp Neurol 148:367–377 Bruno AN, Ricachenevsky FK, Pochmann D, Bonan CD, Battastini AM, Barreto-Chaves ML, Sarkis JJ (2005) Hypothyroidism changes adenine nucleotide hydrolysis in synaptosomes from hippocampus and cerebral cortex of rats in different phases of development. Int J Dev Neurosci 23:37–44 Burgard EC, Sarvey JM (1990) Muscarinic receptor activation facilitates the induction of long-term potentiation (LTP) in the rat dentate gyrus. Neurosci Lett 116:34–39 Calloni GW, Penno CA, Cordova FM, Trentin AG, Neto VM, Leal RB (2005) Congenital hypothyroidism alters the phosphorylation of ERK1/2 and p38MAPK in the hippocampus of neonatal rats. Brain Res Dev Brain Res 154:141–145 Calzà L, Aloe L, Giardino L (1997) Thyroid hormone-induced plasticity in the adult rat brain. Brain Res Bull 44:549–557 Carageorgiou H, Pantos C, Zarros A, Stolakis V, Mourouzis I, Cokkinos D, Tsakiris S (2007) Changes in acetylcholinesterase, Na+, K + -ATPase, and Mg2 + -ATPase activities in the frontal cortex and the hippocampus of hyper- and hypothyroid adult rats. Metabolism 56:1104–1110 Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410:37–40 Chiquet-Ehrismann R, Hagios C, Schenk S (1995) The complexity in regulating the expression of tenascins. Bioessays 17:873–878 Clos J, Legrand C (1990) An interaction between thyroid hormone and nerve growth factor promotes the development of hippocampus, olfactory bulbs and cerebellum: a comparative biochemical study of normal and hypothyroid rats. Growth Factors 3:205–220 Constant EL, de Volder AG, Ivanoiu A, Bol A, Labar D, Seghers A, Cosnard G, Melin J, Daumerie C (2001) Cerebral blood flow and glucose metabolism in hypothyroidism: a positron emission tomography study. J Clin Endocrinol Metab 86:3864–3870 Correia N, Mullally S, Cooke G, Tun TK, Phelan N, Feeney J, Fitzgibbon M, Boran G, O'Mara S, Gibney J (2009) Evidence for a specific defect in hippocampal memory in overt and subclinical hypothyroidism. J Clin Endocrinol Metab 94:3789–3797 Delange F (2000) The role of iodine in brain development. Proc Nutr Soc 59:75–79 Demchenko IT (1983) Blood supply in the conscious brain. Nauka, Leningrad Desouza LA, Ladiwala U, Daniel SM, Agashe S, Vaidya RA, Vaidya VA (2005) Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain. Mol Cell Neurosci 29:414–426 Dong J, Yin H, Liu W, Wang P, Jiang Y, Chen J (2005) Congenital iodine deficiency and hypothyroidism impair LTP and decrease c-fos and c-jun expression in rat hippocampus. Neurotoxicology 26:417–426 Farahvar A, Darwish NH, Sladek S, Meisami E (2007) Marked recovery of functional metabolic activity and laminar volumes in the rat hippocampus and dentate gyrus following postnatal hypothyroid growth retardation: A quantitative cytochrome oxidase study. Exp Neurol 204:556–568 Friauf E, Wenz M, Oberhofer M, Nothwang HG, Balakrishnan V, Knipper M, Löhrke S (2008) Hypothyroidism impairs chloride homeostasis and onset of inhibitory neurotransmission in developing auditory brainstem and hippocampal neurons. Eur J Neurosci 28:2371–2380 Fukunaga K, Miyamoto E (1998) Role of MAP kinase in neurons. Mol Neurobiol 16:79–95 Furley AJ, Morton SB, Manalo D, Karagogeos D, Dodd J, Jessell TM (1990) The axonal glycoprotein TAG-1 is an immunoglobulin superfamily member with neurite outgrowth-promoting activity. Cell 61:157–170 Gabrichidze GO, Lazrishvili NI, Metreveli DS, Bekaya GL, Mitagvariya NP (2007) Local blood flow in the dorsal hippocampus and cerebellar cortex in the offspring of iodine-deficient rats. Neurosci Behav Physiol 37:495–498 Gage FH (2002) Neurogenesis in the adult brain. J Neurosci 22:612–613 García-Fernández LF, Rausell E, Urade Y, Hayaishi O, Bernal J, Muñoz A (1997) Hypothyroidism alters the expression of prostaglandin D2 synthase/beta trace in specific areas of the developing rat brain. Eur J Neurosci 9:1566–1573 Gerges NZ, Alkadhi KA (2004) Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus: MAPK involvement. Hippocampus 14:40–45 Gerges NZ, Stringer JL, Alkadhi KA (2001) Combination of hypothyroidism and stress abolishes early LTP in the CA1 but not dentate gyrus of hippocampus of adult rats. Brain Res 922:250–260 Gilbert ME (2004) Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism. Brain Res Dev Brain Res 148:11–18 Gilbert ME, Paczkowski C (2003) Propylthiouracil (PTU)-induced hypothyroidism in the developing rat impairs synaptic transmission and plasticity in the dentate gyrus of the adult hippocampus. Brain Res Dev Brain Res 145:19–29 Gilbert ME, Sui L, Walker MJ, Anderson W, Thomas S, Smoller SN, Schon JP, Phani S, Goodman JH (2007) Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology 148:92–102 Gilroy J, Meyer JS (1975) Medical Neurology, 2nd edn. MacMillan, New York, pp 239–241 Glinoer D (2007) The importance of iodine nutrition during pregnancy. Public Health Nutr 10:1542–1546 Gu Y, Ihara Y (2000) Evidence that collapsin response mediator protein-2 is involved in the dynamics of microtubules. J Biol Chem 275:17917–17920 Guadaño Ferraz A, Escobar del Rey F, Morreale de Escobar G, Innocenti GM, Berbel P (1994) The development of the anterior commissure in normal and hypothyroid rats. Brain Res Dev Brain Res 81:293–308 Hemmings SJ, Shuaib A (1998) Hypothyroidism-evoked shifts in hippocampal adrenergic receptors: implications to ischemia-induced hippocampal damage. Mol Cell Biochem 185:161–169 Herdegen T, Skene P, Bähr M (1997) The c-Jun transcription factor—bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci 20:227–231 Huang XW, Zhao ZY, Ji C (2005a) Effects of hypothyroidism on apoptosis and the expression of Bcl-2 and Bax gene in the neonatal rat hippocampus neurons. Zhonghua Er Ke Za Zhi 43:48–52 Huang XW, Yang RL, Zhao ZY, Ji C, Yang RW (2005b) Mechanism for apoptosis of hippocampus neuron induced by hypothyroidism in perinatal rats. Zhejiang Da Xue Xue Bao Yi Xue Ban 34:298–303 Huang XW, Yin HM, Ji C, Qin YF, Yang RW, Zhao ZY (2008a) Effects of perinatal hypothyroidism on rat behavior and its relation with apoptosis of hippocampus neurons. J Endocrinol Invest 31:8–15 Huang YH, Tsai MM, Lin KH (2008b) Thyroid hormone dependent regulation of target genes and their physiological significance. Chang Gung Med J 31:325–334 Ibarrola N, Rodríguez-Peña A (1997) Hypothyroidism coordinately and transiently affects myelin protein gene expression in most rat brain regions during postnatal development. Brain Res 752:285–293 Iglesias T, Caubín J, Stunnenberg HG, Zaballos A, Bernal J, Muñoz A (1996) Thyroid hormone-dependent transcriptional repression of neural cell adhesion molecule during brain maturation. EMBO J 15:4307–4316 Iniguez MA, De Lecea L, Guadano-Ferraz A, Morte B, Gerendasy D, Sutcliffe JG, Bernal J (1996) Cell-specific effects of thyroid hormone on RC3/neurogranin expression in rat brain. Endocrinology 137:1032–1041 Juárez de Ku LM, Sharma-Stokkermans M, Meserve LA (1994) Thyroxine normalizes polychlorinated biphenyl (PCB) dose-related depression of choline acetyltransferase (ChAT) activity in hippocampus and basal forebrain of 15-day-old rats. Toxicology 94:19–30 Karin M, Liu Z, Zandi E (1997) AP-1 function and regulation. Curr Opin Cell Biol 9:240–246 Katyare SS, Bangur CS, Howland JL (1994) Is respiratory activity in the brain mitochondria responsive to thyroid hormone action? A critical re-evaluation. Biochem J 302:857–860 Kobayashi H, Koppel AM, Luo Y, Raper JA (1997) A role for collapsin-1 in olfactory and cranial sensory axon guidance. J Neurosci 17:8339–8352 Kobayashi K, Tsuji R, Yoshioka T, Kushida M, Yabushita S, Sasaki M, Mino T, Seki T (2005) Effects of hypothyroidism induced by perinatal exposure to PTU on rat behaviour and synaptic gene expression. Toxicology 212:135–147 Kosaka T, Katsumaru H, Hama K, Wu JY, Heizmann CW (1987) GABAergic neurons containing the Ca2+-binding protein parvalbumin in the rat hippocampus and dentate gyrus. Brain Res 419:119–130 Kouniniotou-Krontiri P, Tsakiris S (1989) Time dependence of Li+ action on acetylcholinesterase activity in correlation with spontaneous quantal release of acetylcholine in rat diaphragm. Jpn J Physiol 39:429–440 Lass P, Slawek J, Derejko M, Rubello D (2008) Neurological and psychiatric disorders in thyroid dysfunctions. The role of nuclear medicine: SPECT and PET imaging. Minerva Endocrinol 33:75–84 Latini S, Pedata F (2001) Adenosine in the central nervous system: release mechanisms and extracellular concentrations. J Neurochem 79:463–484 Legrand J (1982-1983) Thyroid hormones and maturation of the nervous system. J Physiol (Paris) 78:603–652 Madeira MD, Paula-Barbosa M, Cadete-Leite A, Tavares MA (1988) Unbiased estimate of hippocampal granule cell numbers in hypothyroid and in sex-age-matched control rats. J Hirnforsch 29:643–650 Madeira MD, Cadete-Leite A, Andrade JP, Paula-Barbosa MM (1991a) Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: a morphometric study. J Comp Neurol 314:171–186 Madeira MD, Cadete-Leite A, Sousa N, Paula-Barbosa MM (1991b) The supraoptic nucleus in hypothyroid and undernourished rats: an experimental morphometric study. Neuroscience 41:827–839 Madeira MD, Sousa N, Lima-Andrade MT, Calheiros F, Cadete-Leite A, Paula-Barbosa MM (1992) Selective vulnerability of the hippocampal pyramidal neurons to hypothyroidism in male and female rats. J Comp Neurol 322:501–518 Martínez-Galán JR, Pedraza P, Santacana M, Escobar del Ray F, Morreale de Escobar G, Ruiz-Marcos A (1997) Early effects of iodine deficiency on radial glial cells of the hippocampus of the rat fetus. A model of neurological cretinism. J Clin Invest 99:2701–2709 Mash DC, Potter LT (1986) Autoradiographic localization of M1 and M2 muscarine receptors in the rat brain. Neuroscience 19:551–564 Mellström B, Pipaón C, Naranjo JR, Perez-Castillo A, Santos A (1994) Differential effect of thyroid hormone on NGFI-A gene expression in developing rat brain. Endocrinology 135:583–588 Montero-Pedrazuela A, Venero C, Lavado-Autric R, Fernández-Lamo I, García-Verdugo JM, Bernal J, Guadaño-Ferraz A (2006) Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior. Mol Psychiatry 11:361–371 Moreno M, de Lange P, Lombardi A, Silvestri E, Lanni A, Goglia F (2008) Metabolic effects of thyroid hormone derivatives. Thyroid 18:239–253 Moskovkin GN, Marshak TL (1982) Action of hypothyroidism on the metabolic maturation of the pyramidal neurons of the rat hippocampus. Biull Eksp Biol Med 94:112–114 Peeters RP (2008) Thyroid hormones and aging. Hormones (Athens) 7:28–35 Pérez-Delgado MM, Ferres-Torres R, Castañeyra-Perdomo A, González-Hernández T (1987) Effects of hypothyroidism on the karyometric development of pyramidal neurons of the hippocampus (CA1), area 6 and area 17 in the male mouse. J Anat 150:23–29 Rabié A, Patel AJ, Clavel MC, Legrand J (1979) Effect of thyroid deficiency on the growth of the hippocampus in the rat. A combined biochemical and morphological study. Dev Neurosci 2:183–194 Rami A, Rabié A, Patel AJ (1986a) Thyroid hormone and development of the rat hippocampus: cell acquisition in the dentate gyrus. Neuroscience 19:1207–1216 Rami A, Patel AJ, Rabié A (1986b) Thyroid hormone and development of the rat hippocampus: morphological alterations in granule and pyramidal cells. Neuroscience 19:1217–1226 Rami A, Rabie A, Clos J (1989) The time course of hippocampal cholinergic innervation in the developing hypothyroid rat. A combined histochemical and biochemical study of acetylcholinesterase activity. Int J Dev Neurosci 7:301–308 Royland JE, Parker JS, Gilbert ME (2008) A genomic analysis of subclinical hypothyroidism in hippocampus and neocortex of the developing rat brain. J Neuroendocrinol 20:1319–1338 Sastry BS, Phillis JW (1977) Antagonism of biogenic amine-induced depression of cerebral cortical neurones by Na+, K + -ATPase in inhibitors. Can J Physiol Pharmacol 55:170–179 Sawin S, Brodish P, Carter CS, Stanton ME, Lau C (1998) Development of cholinergic neurons in rat brain regions: dose-dependent effects of propylthiouracil-induced hypothyroidism. Neurotoxicol Teratol 20:627–635 Schlessinger AR, Cowan WM, Gottlieb DI (1975) An autoradiographic study of the time of origin and the pattern of granule cell migration in the dentate gyrus of the rat. J Comp Neurol 159:149–175 Schlessinger AR, Cowan WM, Swanson LW (1978) The time of origin of neurons in Ammon’s horn and the associated retrohippocampal fields. Anat Embryol (Berl) 154:153–173 Schoonover CM, Seibel MM, Jolson DM, Stack MJ, Rahman RJ, Jones SA, Mariash CN, Anderson GW (2004) Thyroid hormone regulates oligodendrocyte accumulation in developing rat brain white matter tracts. Endocrinology 145:5013–5020 Stanfield BB, Cowan WM (1979) The development of the hippocampus and dentate gyrus in normal and reeler mice. J Comp Neurol 185:423–459 Sui L, Gilbert ME (2003) Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus. Endocrinology 144:4195–4203 Sui L, Anderson WL, Gilbert ME (2005) Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency. Toxicol Sci 85:647–656 Sui L, Wang F, Li BM (2006) Adult-onset hypothyroidism impairs paired-pulse facilitation and long-term potentiation of the rat dorsal hippocampo-medial prefrontal cortex pathway in vivo. Brain Res 1096:53–60 Sutcliffe JG (1988) The genes for myelin revisited. Trends Genet 4:211–213 Thomas GM, Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5:173–183 Ujihara M, Urade Y, Eguchi N, Hayashi H, Ikai K, Hayaishi O (1988) Prostaglandin D2 formation and characterization of its synthetases in various tissues of adult rats. Arch Biochem Biophys 260:521–531 Wagner JA, Kostyk SK (1990) Regulation of neural cell survival and differentiation by peptide growth factors. Curr Opin Cell Biol 2:1050–1057 White AM, Matthews DB, Best PJ (2000) Ethanol, memory, and hippocampal function: a review of recent findings. Hippocampus 10:88–93 Williams GR (2008) Neurodevelopmental and neurophysiological actions of thyroid hormone. J Neuroendocrinol 20:784–794 Wong CC, Leung MS (2001) Effects of neonatal hypothyroidism on the expressions of growth cone proteins and axon guidance molecules related genes in the hippocampus. Mol Cell Endocrinol 184:143–150 Wotta DR, Wattenberg EV, Langason RB, el-Fakahany EE (1998) M1, M3 and M5 muscarinic receptors stimulate mitogen-activated protein kinase. Pharmacology 56:175–186